Triazolotriazines as kinase inhibitors

ABSTRACT

The present invention is directed to [1,2,4]triazolo[4,3-b][1,2,4]triazines, and pharmaceutical compositions thereof, which are inhibitors of kinases such as c-Met and are useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Prov. App. Ser. Nos.60/835,942, filed Aug. 7, 2006 and 60/861,931, filed Nov. 30, 2006, thedisclosures of which are incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

The present invention is directed to[1,2,4]triazolo[4,3-b][1,2,4]triazines, and pharmaceutical compositionsthereof, which are inhibitors of kinases such as c-Met and are useful inthe treatment of cancer and other diseases related to the dysregulationof kinase pathways.

BACKGROUND OF THE INVENTION

Protein kinases (PKs) are a group of enzymes that regulate diverse,important biological processes including cell growth, survival anddifferentiation, organ formation and morphogenesis, neovascularization,tissue repair and regeneration, among others. Protein kinases exerttheir physiological functions through catalyzing the phosphorylation ofproteins (or substrates) and thereby modulating the cellular activitiesof the substrates in various biological contexts. In addition to thefunctions in normal tissues/organs, many protein kinases also play morespecialized roles in a host of human diseases including cancer. A subsetof protein kinases (also referred to as oncogenic protein kinases), whendysregulated, can cause tumor formation and growth, and furthercontribute to tumor maintenance and progression (Blume-Jensen P et al,Nature 2001, 411(6835):355-365). Thus far, oncogenic protein kinasesrepresent one of the largest and most attractive groups of proteintargets for cancer intervention and drug development.

Protein kinases can be categorized as receptor type and non-receptortype. Receptor tyrosine kinases (RTKs) have an extracellular portion, atransmembrane domain, and an intracellular portion, while non-receptortyrosine kinases are entirely intracellular. RTK mediated signaltransduction is typically initiated by extracellular interaction with aspecific growth factor (ligand), typically followed by receptordimerization, stimulation of the intrinsic protein tyrosine kinaseactivity, and receptor transphosphorylation. Binding sites are therebycreated for intracellular signal transduction molecules and lead to theformation of complexes with a spectrum of cytoplasmic signalingmolecules that facilitate the appropriate cellular response such as celldivision, differentiation, metabolic effects, and changes in theextracellular microenvironment

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, includesEGFR, HER2, HER3 and HER4, and bind such ligands as epithelial growthfactor (EGF), TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. Asecond family of RTKs, designated the insulin subfamily, includes theINS-R, the IGF-1R and the IR-R. A third family, the “PDGF” subfamily,includes the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, referred to as the FLK subfamily, encompassesthe Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), thefetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1).Two other subfamilies of RTKs have been designated as the FGF receptorfamily (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-Met, Ronand Sea). For a detailed discussion of protein kinases, see for example,Blume-Jensen, P. et al., Nature. 2001, 411(6835):355-365, and Manning,G. et al., Science. 2002, 298(5600):1912-1934.

The non-receptor type of tyrosine kinases is also composed of numeroussubfamilies, including Src, Btk, Abl, Fak, and Jak. Each of thesesubfamilies can be further subdivided into multiple members that havebeen frequently linked to oncogenesis. The Src family, for example, isthe largest and includes Src, Fyn, Lck and Fgr among others. For adetailed discussion of these kinases, see Bolen J B. Nonreceptortyrosine protein kinases. Oncogene. 1993, 8(8):2025-31.

A significant number of tyrosine kinases (both receptor and nonreceptor)are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosinekinase inhibitors in cancer therapy. Clin Biochem. 2004, 37(7):618-35.).Clinical studies suggest that overexpression or dysregulation oftyrosine kinases may also be of prognostic value. For example, membersof the HER family of RTKs have been associated with poor prognosis inbreast, colorectal, head and neck and lung cancer. Mutation of c-Kittyrosine kinase is associated with decreased survival ingastrointestinal stromal tumors. In acute myelogenous leukemia, Flt-3mutation predicts shorter disease free survival. VEGFR expression, whichis important for tumor angiogenesis, is associated with a lower survivalrate in lung cancer. Tie-1 kinase expression inversely correlates withsurvival in gastric cancer. BCR-Abl expression is an important predictorof response in chronic myelogenous leukemia and Src tyrosine kinase isan indicator of poor prognosis in all stages of colorectal cancer.

c-Met, a proto-oncogene, is a member of a distinct subfamily ofheterodimeric receptor tyrosine kinases which include Met, Ron, and Sea(Birchmeier, C. et al., Nat. Rev. Mol. Cell. Biol. 2003, 4(12):915-925;Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26). The onlyhigh affinity ligand for c-Met is the hepatocyte growth factor (HGF),also known as scatter factor (SF). Binding of HGF to c-Met inducesactivation of the receptor via autophosphorylation resulting in anincrease of receptor dependent signaling. Both c-Met and HGF are widelyexpressed in a variety of organs, but their expression is normallyconfined to the cells of epithelial and mesenchymal origin,respectively. The biological functions of c-Met (or c-Met signalingpathway) in normal tissues and human malignancies such as cancer havebeen well documented (Christensen, J. G. et al., Cancer Lett. 2005,225(1):1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6):284-292).

HGF and c-Met are each required for normal mammalian development, andabnormalities reported in both HGF- and c-Met-null mice are consistentwith proximity of embryonic expression and epithelial-mesenchymaltransition defects during organ morphogenesis (Christensen, J. G. etal., Cancer Lett. 2005, 225(1):1-26). Consistent with these findings,the transduction of signaling and subsequent biological effects ofHGF/c-Met pathway have been shown to be important forepithelial-mesenchymal interaction and regulation of cell migration,invasion, cell proliferation and survival, angiogenesis, morphogenesisand organization of three-dimensional tubular structures (e.g. renaltubular cells, gland formation) during development. The specificconsequences of c-Met pathway activation in a given cell/tissue arehighly context-dependent.

Dysregulated c-Met pathway plays important and sometimes causative (inthe case of genetic alterations) roles in tumor formation, growth,maintenance and progression (Birchmeier, C. et al., Nat. Rev. Mol. Cell.Biol. 2003, 4(12):915-925; Boccaccio, C. et al., Nat. Rev. Cancer 2006,6(8):637-645; Christensen, J. G. et al., Cancer Lett. 2005,225(1):1-26). HGF and/or c-Met are overexpressed in significant portionsof most human cancers, and are often associated with poor clinicaloutcomes such as more aggressive disease, disease progression, tumormetastasis and shortened patient survival. Further, patients with highlevels of HGF/c-Met proteins are more resistance to chemotherapy andradiotherapy. In addition to the abnormal HGF/c-Met expression, c-Metreceptor can also be activated in cancer patients through geneticmutations (both germline and somatic) and gene amplification. Althoughgene amplification and mutations are the most common genetic alterationsthat have been reported in patients, the receptor can also be activatedby deletions, truncations, gene rearrangement, as well as abnormalreceptor processing and defective negative regulatory mechanisms.

The various cancers in which c-Met is implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, cervical,cholangiocarcinoma, colorectal, esophageal, gastric, head and neck,kidney, liver, lung, nasopharygeal, ovarian, pancreas, prostate,thyroid); musculoskeletal sarcomas (e.g., osteosarcaoma, synovialsarcoma, rhabdomyosarcoma); soft tissue sarcomas (e.g.,MFH/fibrosarcoma, leiomyosarcoma, kaposi's sarcoma); hematopoieticmalignancies (e.g., multiple myeloma, lymphomas, adult T cell leukemia,acute myelogenous leukemia, chronic myeloid leukemia); and otherneoplasms (e.g., glioblastomas, astrocytomas, melanoma, mesothelioma andWilm's tumor (www.vai.org/met/; Christensen, J. G. et al., Cancer Lett.2005, 225(1):1-26).

The notion that the activated c-Met pathway contributes to tumorformation and progression and could be a good target for effectivecancer intervention has been further solidified by numerous preclinicalstudies (Birchmeier, C. et al., Nat. Rev. Mol. Cell. Biol. 2003,4(12):915-925; Christensen, J. G. et al., Cancer Lett. 2005,225(1):1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6):284-292).For example, studies showed that the tpr-met fusion gene, overexpressionof c-met and activated c-met mutations all caused oncogenictransformation of various model cell lines and resulted in tumorformation and metastasis in mice. More importantly, significantanti-tumor (sometimes tumor regression) and anti-metastasis activitieshave been demonstrated in vitro and in vivo with agents thatspecifically impair and/or block HGF/c-Met signaling. Those agentsinclude anti-HGF and anti-c-Met antibodies, HGF peptide antagonists,decoy c-Met receptor, c-Met peptide antagonists, dominant negative c-Metmutations, c-Met specific antisense oligonucleotides and ribozymes, andselective small molecule c-Met kinase inhibitors (Christensen, J. G. etal., Cancer Lett. 2005, 225(1):1-26).

In addition to the established role in cancer, abnormal HGF/c-Metsignaling is also implicated in atherosclerosis, lung fibrosis, renalfibrosis and regeneration, liver diseases, allergic disorders,inflammatory and autoimmune disorders, cerebrovascular diseases,cardiovascular diseases, conditions associated with organtransplantation (Ma, H. et al., Atherosclerosis. 2002, 164(1):79-87;Crestani, B. et al., Lab. Invest. 2002, 82(8):1015-1022; Sequra-Flores,A. A. et al., Rev. Gastroenterol. Mex. 2004, 69(4)243-250; Morishita, R.et al., Curr. Gene Ther. 2004, 4(2)199-206; Morishita, R. et al.,Endocr. J. 2002, 49(3)273-284; Liu, Y., Curr. Opin. Nephrol. Hypertens.2002, 11(1):23-30; Matsumoto, K. et al., Kidney Int. 2001,59(6):2023-2038; Balkovetz, D. F. et al., Int. Rev. Cytol. 1999,186:225-250; Miyazawa, T. et al., J. Cereb. Blood Flow Metab. 1998,18(4)345-348; Koch, A. E. et al., Arthritis Rheum. 1996,39(9):1566-1575; Futamatsu, H. et al., Circ. Res. 2005, 96(8)823-830;Eguchi, S. et al., Clin. Transplant. 1999, 13(6)536-544).

Despite the important/causative roles that the c-Met pathway plays inthe above described human diseases including cancer, there are no c-Metinhibitors or antagonists that are currently available for treatingthese human disorders that associate with abnormal HGF/c-Met signaling.Therefore, there is a clear unmet medical need to develop new compoundsas inhibitors of c-Met kinase and other kinases. The compounds,compositions, and pharmaceutical methods provided herein help meet thisneed.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds having Formula I:

or pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent variables are provided herein.

The present invention further provides compositions comprising at leastone compound of Formula I and at least one pharmaceutically acceptablecarrier.

The present invention further provides methods of inhibiting activity ofa receptor or non-receptor tyrosine kinase by contacting the kinase witha compound of Formula I, or pharmaceutically acceptable salt thereof.

The present invention further provides methods of inhibiting theHGF/c-Met kinase signaling pathway in a cell by contacting the cell witha compound of Formula I, or pharmaceutically acceptable salt thereof.

The present invention further provides methods of inhibiting theproliferative activity of a cell by contacting the cell with a compoundof Formula I, or pharmaceutically acceptable salt thereof.

The present invention further provides methods of inhibiting tumorgrowth in a patient by administering to the patient a therapeuticallyeffective amount of a compound of Formula I, or pharmaceuticallyacceptable salt thereof.

The present invention further provides methods of inhibiting tumormetastasis in a patient comprising administering to the patient atherapeutically effective amount of a compound of Formula I, orpharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ina patient, wherein the disease is associated with dysregulation of theHGF/c-MET signaling pathway, by administering to the patient atherapeutically effective amount of a compound of Formula I, orpharmaceutically acceptable salt thereof.

The present invention further provides methods of treating cancer in apatient by administering to the patient a therapeutically effectiveamount of a compound of Formula I, or pharmaceutically acceptable saltthereof.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds that areinhibitors of kinases, including receptor tyrosine kinases such as thoseof the Met subfamily, having Formula J:

or pharmaceutically acceptable salts or prodrugs thereof, wherein:

Cy¹ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4, or 5 -W—X—Y—Z;

Cy² is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4, or 5 -W′—X′—Y′—Z′;

A is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,CN, NO₂, OR^(A), SR^(A), C(O)R^(B), C(O)NR^(C)R^(D), C(O)OR^(A),OC(O)R^(B), OC(O)NR^(C)R^(D), NR^(C)R^(D), NR^(C)(O)R^(B),NR^(C)C(O)NR^(C)R^(D), NR^(C)C(O)OR^(A), S(O)R^(B), S(O)NR^(C)R^(D),S(O)₂R^(B), NR^(C)S(O)₂R^(B), or S(O)₂NR^(C)R^(D);

R¹ and R² together with the carbon atom to which they are attached forma 3- to 7-membered cycloalkyl group or 3- to 7-membered heterocycloalkylgroup, each optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from Q, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(g))NR^(c)R^(d)NR^(c)C(═NR^(g))NR^(c)R^(d), P(R^(f))₂, P(OR^(e))₂,P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl is optionally substituted with 1,2, or 3 substituents selected from Q, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d), P(R^(f))₂,P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(e),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

Q is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4, or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1),C(═NR^(g1))NR^(c1)R^(d1), NR^(c1)C(═NR^(g1))NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1);

W and W′ are independently absent or independently selected from C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, O, S, NR^(h), CO, COO,CONR^(h), SO, SO₂, SONR^(h) and NR^(h)CONR^(i), wherein each of the C₁₋₆alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionally substitutedby 1, 2 or 3 substituents independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, and C₂₋₈ dialkylamino;

X and X′ are independently absent or independently selected from C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene,heteroarylene, and heterocycloalkylene, wherein each of the C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene,heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2or 3 substituents independently selected from halo, CN, NO₂, OH, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₈ alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR^(j),C(O)NR^(h)R^(i), amino, C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;

Y and Y′ are independently absent or independently selected from C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, O, S, NR^(h), CO, COO,CONR^(h), SO, SO₂, SONR^(h), and NR^(h)CONR^(i), wherein each of theC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted by 1, 2 or 3 substituents independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino,C₁₋₆ alkylamino, and C₂₋₈ dialkylamino;

Z and Z′ are independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2),C(═NR^(g2))NR^(c2)R^(d2)NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

wherein two adjacent —W—X—Y—Z, together with the atoms to which they areattached, optionally form a fused 4-, 5-, 6-, or 7-membered cycloalkylring or a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring, eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN,NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl;

wherein two adjacent —W′—X′—Y′—Z′, together with the atoms to which theyare attached, optionally form a fused 4-, 5-, 6-, or 7-memberedcycloalkyl ring or a fused 4-, 5-, 6-, or 7-membered heterocycloalkylring, each optionally substituted by 1, 2, or 3 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl;

R^(A) is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein said C₁₋₄alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, is optionally substituted with 1,2, or 3 substituents independently selected from OH, CN, amino, halo,and C₁₋₄ alkyl;

R^(B) is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein said C₁₋₄alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, is optionally substituted with 1,2, or 3 substituents independently selected from OH, CN, amino, halo,and C₁₋₄ alkyl;

R^(C) and R^(D) are independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, or C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄alkynyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, and C₁₋₄ alkyl;

or R^(C) and R^(D) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, and C₁₋₄ alkyl;

R^(a), R^(a1), R^(a2), are R^(a3) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆haloalkoxy;

R^(b), R^(b1), R^(b2), and R^(b3) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy;

R^(c) and R^(d) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy;

R^(c1) and R^(d1) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy;

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy;

R^(c2) and R^(d2) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl,arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl, whereinsaid C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,C(O)OR^(a3), C(O)R^(b3), S(O)₂R^(b3), alkoxyalkyl, and alkoxyalkoxy;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl,heteroaryl, C(O)OR³³, C(O)R^(b3), S(O)₂R^(b3), alkoxyalkyl, andalkoxyalkoxy.

R^(e) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, (C₁₋₆ alkoxy)-C₁₋₆alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl;

R^(f) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;

R^(g), R^(g1), and R^(g2) are independently selected from H, CN, andNO₂;

R^(h) and R^(i) are independently selected from H and C₁₋₆ alkyl; and

R^(j) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.

In some embodiments, Cy¹ is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4, or 5 -W—X—Y—Z.

In some embodiments, Cy¹ is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4, or 5-Z.

In some embodiments, Cy¹ is aryl or heteroaryl, each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, OH, and C₁₋₄ alkoxy.

In some embodiments, Cy¹ is phenyl or quinolinyl, each optionallysubstituted by 1, 2, 3, 4, or 5 -W—X—Y—Z.

In some embodiments, Cy¹ is phenyl optionally substituted by 1, 2, 3, 4,or 5 -W—X—Y—Z.

In some embodiments, Cy¹ is quinolinyl optionally substituted by 1, 2,3, 4, or 5-W—X—Y—Z.

In some embodiments, Cy¹ is quinolinyl.

In some embodiments, Cy² is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4, or 5 -W′—X′—Y′—Z′.

In some embodiments, Cy² is phenyl optionally substituted by 1, 2, 3, 4,or 5-W′—X′.

In some embodiments, Cy² is phenyl optionally substituted by 1, 2, 3, 4,or 5-Z′.

In some embodiments, Cy² is phenyl optionally substituted by 1, 2, 3, 4,or 5-CONR^(h)—X′—Y′—Z′.

In some embodiments, A is H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(A), or NR^(C)R^(D).

In some embodiments, A is H or NR^(C)R^(D).

In some embodiments, R¹ and R² together with the carbon atom to whichthey are attached form a 3- to 7-membered cycloalkyl group optionallysubstituted by 1, 2, 3, 4, or 5 substituents independently selected fromQ, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl is optionallysubstituted with 1, 2, or 3 substituents selected from Q, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, R¹ and R² together with the carbon atom to whichthey are attached form a cyclopropyl group optionally substituted by 1,2, 3, 4, or 5 substituents independently selected from Q, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl is optionallysubstituted with 1, 2, or 3 substituents selected from Q, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d)NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, R¹ and R² together with the carbon atom to whichthey are attached form a 3- to 7-membered cycloalkyl group.

In some embodiments, R¹ and R² together with the carbon atom to whichthey are attached form a cyclopropyl group.

In some embodiments, Q is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1),NR^(c1)C(O)OR^(a1), C(═NR^(g1))NR^(c1)R^(d1),NR^(c1)C(═NR^(g1))NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments, W is CONR^(h).

In some embodiments, —W—X—Y—Z is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2),C(═NR^(g2))NR^(c2)R^(d2), NR^(c2)C(═NR^(g2))NR^(c2)R^(b2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2).

In some embodiments, —W—X—Y—Z is H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2),S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ aryl, cycloalkyl, heteroaryl, andheterocycloalkyl are optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, —W—X—Y—Z is H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2),S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ aryl, cycloalkyl, heteroaryl, andheterocycloalkyl are optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2)NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, —W—X—Y—Z is H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, OR^(a2), C(O)R^(b2), and C(O)NR^(c2)R^(d2), wherein said C₁₋₆alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, —W—X—Y—Z is H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, OR^(a2), C(O)R^(b2), and C(O)NR^(c2)R^(d2).

In some embodiments, at least one —W—X—Y—Z is C(O)NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2),C(═NR^(g2))NR^(c2)R^(d2), NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2),S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ aryl, cycloalkyl, heteroaryl, andheterocycloalkyl are optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2),S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,wherein said C₁₋₆ alkyl, C₂₋₆ aryl, cycloalkyl, heteroaryl, andheterocycloalkyl are optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), C(O)R^(b2), and C(O)NR^(c2)R^(d2), whereinsaid C₁₋₆ alkyl is optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2)S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, —W′—X′—Y′—Z′ is H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), C(O)R^(b2), and C(O)NR^(c2)R^(d2).

In some embodiments, at least one —W′—X′—Y′—Z′ is C(O)NR^(c2)R^(d2).

In some embodiments, R^(c2) and R^(d2) are independently selected fromH, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy.

In some embodiments, Z and Z′ are independently selected from H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2),C(═NR^(g2))NR^(c2)R^(d2), NR^(c2)C(NR^(g2))NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

In some embodiments, the compounds of the invention have Formula II:

In some embodiments, the compounds of the invention have Formula IIIa orIIIb:

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

It is further intended that the compounds of the invention are stable.As used herein “stable” refers to a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and preferably capable of formulation into an efficacioustherapeutic agent.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms.

As used herein, the term “alkylene” refers to a linking alkyl group.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, and the like.

As used herein, “alkenylene” refers to a linking alkenyl group.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like.

As used herein, “alkynylene” refers to a linking alkynyl group.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 carbonatoms.

As used herein, “arylene” refers to a linking aryl group.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)ring systems, including spirocycles. In some embodiments, cycloalkylgroups can have from 3 to about 20 carbon atoms, 3 to about 14 carbonatoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkylgroups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2triple bonds. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, for example, benzo derivatives ofpentane, pentene, hexane, and the like. A cycloalkyl group having one ormore fused aromatic rings can be attached though either the aromatic ornon-aromatic portion. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized, for example, having an oxo or sulfidosubstituent. Example cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,adamantyl, and the like.

As used herein, “cycloalkylene” refers to a linking cycloalkyl group.

As used herein, a “heteroaryl” group refers to an aromatic heterocyclehaving at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in aheteroaryl group can also be oxidized to form an N-oxo moiety. Examplesof heteroaryl groups include without limitation, pyridyl, N-oxopyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl,isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and thelike. In some embodiments, the heteroaryl group has from 1 to about 20carbon atoms, and in further embodiments from about 3 to about 20 carbonatoms. In some embodiments, the heteroaryl group contains 3 to about 14,3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, theheteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heteroarylene” refers to a linking heteroaryl group.

As used herein, “heterocycloalkyl” refers to a non-aromatic heterocyclewhere one or more of the ring-forming atoms is a heteroatom such as anO, N, or S atom. Heterocycloalkyl groups can include mono- or polycyclic(e.g., having 2, 3 or 4 fused rings) ring systems as well asspirocycles. Example “heterocycloalkyl” groups include morpholino,thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles such as indolene and isoindolenegroups. A heterocycloalkyl group having one or more fused aromatic ringscan be attached though either the aromatic or non-aromatic portion. Insome embodiments, the carbon atoms or heteroatoms in the heterocyclyl orheterocycle ring can be oxidized (to form, e.g., a carbonyl, sulfinyl,sulfonyl, or other oxidized nitrogen or sulfur linkage) or a nitrogenatom can be quaternized. In some embodiments, the heterocycloalkyl grouphas from 1 to about 20 carbon atoms, and in further embodiments fromabout 3 to about 20 carbon atoms. In some embodiments, theheterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about7, or 5 to 6 ring-forming atoms. In some embodiments, theheterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2heteroatoms. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 triple bonds.

As used herein, “heterocycloalkylene” refers to a linkingheterocycloalkyl group.

As used herein, “heterocycloalkylene” refers to a linkingheterocycloalkyl group.

As used herein, “arylcycloalkyl” refers to cycloalkyl group substitutedby an aryl group.

As used herein, “arylheterocycloalkyl” refers to a heterocycloalkylgroup substituted by an aryl group.

As used herein, “arylheteroaryl” refers to a heteroaryl groupsubstituted by an aryl group.

As used herein, “biaryl” refers to an aryl group substituted by anotheraryl group.

As used herein, “heteroarylcycloalkyl” refers to a cycloalkyl groupsubstituted by a heteroaryl group.

As used herein, “heteroarylheterocycloalkyl” refers to aheterocycloalkyl group substituted by a heteroaryl group.

As used herein, “heteroarylaryl” refers to an aryl group substituted bya heteroaryl group.

As used herein, “biheteroaryl” refers to a heteroaryl group substitutedby another heteroaryl group.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “hydroxyalkyl” refers to an alkyl group substituted witha hydroxyl group.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “alkoxyalkyl” refers to an alkyl group substituted by analkoxy group.

As used herein, “alkoxyalkoxy” refers to an alkoxy group substituted byalkoxy.

As used herein, “haloalkoxy” refers to an —O-(haloalkyl) group.

As used herein, “arylalkyl” refers to alkyl substituted by aryl and“cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An examplearylalkyl group is benzyl.

As used herein, “heteroarylalkyl” refers to alkyl substituted byheteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted byheterocycloalkyl.

As used herein, “amino” refers to NH₂.

As used herein, “alkylamino” refers to an amino group substituted by analkyl group.

As used herein, “dialkylamino” refers to an amino group substituted bytwo alkyl groups.

As used herein, “halosulfanyl” refers to a sulfur group having one ormore halogen substituents. Example halosulfanyl groups includepentahalosulfanyl groups such as SF₅.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term “compound,” as used herein, is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted.

In some embodiments, the compounds of the invention, and salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compound of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The compounds of the invention, and salts thereof, can also be preparedin combination with solvent or water molecules to form solvates andhydrates by routine methods.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

The novel compounds of the present invention can be prepared in avariety of ways known to one skilled in the art of organic synthesis.The compounds of the present invention can be synthesized using themethods as hereinafter described below, together with synthetic methodsknown in the art of synthetic organic chemistry or variations thereon asappreciated by those skilled in the art.

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given; other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography.

Preparation of Compounds can Involve the Protection and Deprotection ofVarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Resolution ofracemic mixtures can also be carried out by elution on a column packedwith an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

The compounds of the invention can be prepared, for example, using thereaction pathways and techniques as described below.

A series of triazolotriazine derivatives of formulas 3 and 4 can beprepared by the method outlined in Scheme 1. Reaction ofoxo-acetaldehyde 1 with 3,4-diaminotriazole 2 can afford the compounds 3and 4.

The 3,4-diaminotriazole 2 can be prepared by the method outlined inScheme 2. For example, a mixture of a carboxylic acid 5 and1,3-diaminoguanine 6 can be heated to form 2. Alternatively, thecarboxylic acid 5 can be converted to the corresponding chloride 7 whichreacts with hydrazide HBr salt 8 to give the acid hydrazide 9 which, inturn, can be transformed to the 3,4-diaminotriazole 2 by treatment withhydrazine.

In a further alternative route, 3,4-diaminotriazole 2 can also beprepared by the method outlined in Scheme 3. Treatment of compound 10with bromocyanide in the presence of a base such as potassium carbonateor sodium carbonate can give the 2-amino-oxadiazole 11 which, in turn,can be converted to the 3,4-diaminotriazole 2 by reaction withhydrazine.

A series of triazolotriazine derivatives of formula 3 could be preparedaccording to the procedures outlined in Scheme 4. Semicarbazide 13 couldbe prepared by reaction of the semicarbazide hydrochloride withoxo-acetal 12 which could be obtained from oxo-acetaldehyde 1 bytreatment with triethylformate. Intramolecular ring closure of 13produced the triazinone 14 which could be transferred to thecorresponding chloride 15 by reflux with POCl₃ in inert solvent such aschloroform, 1,2-dichloroethane or toluene in a presence of a catalyticamount of DMF. Replacement of the chlorine in 15 with hydrazine yieldcompound 16 which could be converted to the triazine 3 by reaction withthe carboxylic acid 5 in presence of POCl₃. Alternatively, reaction of16 with the chloride 7 could produce compound 17. Intramolecular ringclosure of 17 in hot POCl₃ affords the triazolotriazine 3.

Alternatively, the triazinone 14 can be prepared according to theprocedure outlined in Scheme 5. The oxo-acetaldehyde 1 can betransformed to the corresponding oxo-oxime 18. Reaction of 18 withsemicarbazide can afford the compound 19. Hydrolysis of the oxime in 19following intramolecular ring closure can afford the triazinone 14.

In a similar manner, the triazolotriazine 3 can be prepared by themethods outlined in Scheme 6. Amide 21, obtained by coupling of the acid20 with N,O-dimethylhydroxylamine in presence of BOP or DCI, can beconverted to the corresponding ketone 23 by reaction with lithium agent22 which, in turn, can be produced by treatment of 1,3-dithiane andn-butyl lithium at low temperature. Reflux of the ketone 23 withthiosemicarbazide in an inert solvent such as ethanol or toluene and inthe presence of an acid such as 4-toluenesulfonic acid can afford thecompound 24. Alkylation of compound 24 with methyl iodide in thepresence of a suitable base such as cesium carbonate, potassiumcarbonate, sodium carbonate, or sodium hydroxide can give triazine 25which, in turn, can be transformed to the compound 16. Thetriazolotriazine 3 can be prepared from 16 as previously described.

A series of triazolotriazine derivatives of formula 4 can further beprepared according to the procedures outlined in Scheme 7. Compound 26can be conveniently obtained by reflux of oxo-acetaldehyde 1 withthiosemicarbazide hydrochloride in a solvent mixture of ethanol andwater. Alkylation of compound 26 with methyl iodide in the presence of abase such as cesium carbonate, potassium carbonate, sodium carbonate, orsodium hydroxide can produce triazine 27 which can be transformed tocompound 28 and the triazolotriazine 4 as previously described.

A series of triazolotriazine derivatives of formula 3 can be furtherprepared according to the procedures outlined in Scheme 8. Hydrazinederivative 31 can be obtained from the chloride 29 by treatment withethyl hydrazinecarbimidothioate hydrobromide followed by replacementwith hydrazine. Reaction of 31 with acid chloride 7 can produce thetriazinone 32 which can be transformed to the corresponding chloride 33.Suzuki Coupling of 33 can afford the triazolotriazine derivative 34.

A series of triazolotriazine derivatives of formula 40 can be preparedaccording to the procedures outlined in Scheme 9. Treatment of the acid20 with thiosemicarbazide in the presence of a base such as sodiumcarbonate, potassium carbonate, sodium hydroxide, or potassium hydroxidecan give the compound 35 which, in turn, can convert to compound 36 byalkylation with methyl iodide. Triazinone 38 can be obtained from 36 byreplacement with hydrazine followed by reaction with the chloride 7.Compound 38 can be transformed to the corresponding chloride 39 bytreatment with POCl₃ or SOCl₂. Reaction of 39 with an appropriate aminecan afford the triazolotriazine derivative 40.

Methods of Use

Compounds of the invention can modulate activity of protein kinases.Example protein kinases modulated by the compounds of the inventioninclude RTKs of the HER subfamily (e.g., EGFR, HER2, HER3 and HER4), ofthe insulin subfamily (e.g., INS-R, the IGF-1R and the IR-R), of thePDGF subfamily (e.g., the PDGF alpha and beta receptors, CSFIR, c-kitand FLK-II), of the FLK subfamily (e.g., Kinase insert Domain-Receptorfetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) andthe fms-like tyrosine kinases 1 and 3 (flt-1 and flt-3)), of the FGFreceptor family (e.g., FGFR1, FGFR2, FGFR3 and FGFR4), of the Metsubfamily (e.g., c-Met, Ron amd Sea), and of the Src, Abl, and Jak(e.g., Jak1, Jak2, and Jak3) subfamilies. In some embodiments, thecompounds of the invention modulate activity of c-Met.

The term “modulate” is meant to refer to an ability to increase ordecrease activity of an enzyme or receptor. Modulation can occur invitro or in vivo. Modulation can further occur in a cell. Accordingly,compounds of the invention can be used in methods of modulating aprotein kinase, such as an RTK, by contacting the enzyme (or cell orsample containing the enzyme) with any one or more of the compounds orcompositions described herein.

In some embodiments, compounds of the present invention can act asinhibitors of one or more protein kinases. In some further embodiments,compounds of the invention can be used in methods of inhibiting an RTKof the Met or FLK subfamilies. In yet further embodiments, the compoundsof the invention can be used in methods of inhibiting c-Met, KDR, orflt-3 kinase. In yet further embodiments, the compounds of the inventioncan be used as inhibitors c-Met. In yet further embodiments, thecompounds of the invention are selective inhibitors of c-Met.

Treatment of a cell (in vitro or in vivo) that expresses a proteinkinase with a compound of the invention can result in inhibiting theligand/kinase signaling pathway and inhibiting downstream events relatedto the signaling pathway such as cellular proliferation and increasedcell motility. For example, the compounds of the invention can blockand/or impair the biochemical and biological processes resulting fromc-Met pathway activation, including, but not limited to, c-Met kinaseactivation (e.g. c-Met phosphorylation) and signaling (activation andrecruitment of cellular substrates such as Gab1, Grb2, Shc and c-Cbl andsubsequent activation of a number of signal transducers including PI-3kinase, PLC-γ, STATs, ERK1/2 and FAK), cell proliferation and survival,cell motility, migration and invasion, metastasis, angiogenesis, and thelike. Thus, the present invention further provides methods of inhibitinga ligand/kinase signaling pathway such as the HGF/c-Met kinase signalingpathway in a cell by contacting the cell with a compound of theinvention. The present invention further provides methods of inhibitingproliferative activity of a cell or inhibiting cell motility bycontacting the cell with a compound of the invention.

The present invention further provides methods of treating diseasesassociated with a dysregulated kinase signaling pathway, includingabnormal activity and/or overexpression of the protein kinase, in anindividual (e.g., patient) by administering to the individual in need ofsuch treatment a therapeutically effective amount or dose of a compoundof the present invention or a pharmaceutical composition thereof. Insome embodiments, the dysregulated kinase is of the Met family (e.g.,c-Met, Ron, or Sea). In some embodiments, the dysregulated kinase isoverexpressed in the diseased tissue of the patient. In someembodiments, the dysregulated kinase is abnormally active in thediseased tissue of the patient. Dysregulation of c-Met and the HGF/c-Metsignaling pathway is meant to include activation of the enzyme throughvarious mechanisms including, but not limited to, HGF-dependentautocrine and paracrine activation, c-met gene overexpression andamplification, point mutations, deletions, truncations, rearrangement,as well as abnormal c-Met receptor processing and defective negativeregulatory mechanisms.

In some embodiments, the compounds of the invention are useful intreating diseases such as cancer, atherosclerosis, lung fibrosis, renalfibrosis and regeneration, liver disease, allergic disorder,inflammatory disease, autoimmune disorder, cerebrovascular disease,cardiovascular disease, or condition associated with organtransplantation. In further embodiments, the compounds of the inventioncan be useful in methods of inhibiting tumor growth or metastasis of atumor in a patient.

Example cancers treatable by the methods herein include bladder cancer,breast cancer, cervical cancer, cholangiocarcinoma cancer, colorectalcancer, esophageal cancer, gastric cancer, head and neck cancer, cancerof the kidney, liver cancer, lung cancer, nasopharygeal cancer, ovariancancer, pancreatic cancer, prostate cancer, thyroid cancer,osteosarcoma, synovial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma,leiomyosarcoma, Kaposi's sarcoma, multiple myeloma, lymphoma, adult Tcell leukemia, acute myelogenous leukemia, chronic myeloid leukemia,glioblastoma, astrocytoma, melanoma, mesothelioma, or Wilm's tumor, andthe like.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a compound of the invention with a protein kinaseincludes the administration of a compound of the present invention to anindividual or patient, such as a human as well as, for example,introducing a compound of the invention into a sample containing acellular or purified preparation of the protein kinase.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder; and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, chemotherapeutics, anti-cancer agents, cytotoxicagents, or anti-cancer therapies (e.g., radiation, hormone, etc.), canbe used in combination with the compounds of the present invention fortreatment of the diseases, disorders or conditions described herein. Theagents or therapies can be administered together with the compounds ofthe invention (e.g., combined into a single dosage form), or the agentsor therapies can be administered simultaneously or sequentially byseparate routes of administration.

Suitable anti-cancer agents include kinase inhibiting agents includingtrastuzumab (Herceptin), imatinib (Gleevec), gefitinib (Iressa),erlotinib hydrochloride (Tarceva), cetuximab (Erbitux), bevacizumab(Avastin), sorafenib (Nexavar), sunitinib (Sutent), and RTK inhibitorsdescribed in, for example, WO 2005/004808, WO 2005/004607, WO2005/005378, WO 2004/076412, WO 2005/121125, WO 2005/039586, WO2005/028475, WO 2005/040345, WO 2005/039586, WO 2003/097641, WO2003/087026, WO 2005/040154, WO 2005/030140, WO 2006/014325, WO2005/070891, WO 2005/073224, WO 2005/113494, and U.S. Pat. App. Pub.Nos. 2005/0085473, 2006/0046991, and 2005/00753402

Suitable chemotherapeutic or other anti-cancer agents further include,for example, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (Taxol™), mithramycin, deoxyco-formycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).Further antibody therapeutics include antibodies to tyrosine kinasesand/or their ligands such as anti-HGF antibodies and/or anti-c-Metantibodies. The term “antibody” is meant to include whole antibodies(e.g., monoclonal, polyclonal, chimeric, humanized, human, etc.) as wellas antigen-binding fragments thereof.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Other anti-cancer agents include anti-cancer vaccines such as dendriticcells, synthetic peptides, DNA vaccines and recombinant viruses.

Methods for the safe and effective administration of most of the aboveagents are known to those skilled in the art. In addition, theiradministration is described in the standard literature. For example, theadministration of many of the chemotherapeutic agents is described inthe “Physicians' Desk Reference” (PDR, e.g., 1996 edition, MedicalEconomics Company, Montvale, N.J.), the disclosure of which isincorporated herein by reference as if set forth in its entirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions which is acombination of a compound of the invention and a pharmaceuticallyacceptable carrier. These compositions can be prepared in a manner wellknown in the pharmaceutical art, and can be administered by a variety ofroutes, depending upon whether local or systemic treatment is desiredand upon the area to be treated. Administration may be topical(including ophthalmic and to mucous membranes including intranasal,vaginal and rectal delivery), pulmonary (e.g., by inhalation orinsufflation of powders or aerosols, including by nebulizer;intratracheal, intranasal, epidermal and transdermal), ocular, oral orparenteral. Methods for ocular delivery can include topicaladministration (eye drops), subconjunctival, periocular or intravitrealinjection or introduction by balloon catheter or ophthalmic insertssurgically placed in the conjunctival sac. Parenteral administrationincludes intravenous, intraarterial, subcutaneous, intraperitoneal orintramuscular injection or infusion; or intracranial, e.g., intrathecalor intraventricular, administration. Parenteral administration can be inthe form of a single bolus dose, or may be, for example, by a continuousperfusion pump. Pharmaceutical compositions and formulations for topicaladministration may include transdermal patches, ointments, lotions,creams, gels, drops, suppositories, sprays, liquids and powders.Conventional pharmaceutical carriers, aqueous, powder or oily bases,thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, for example see InternationalPatent Application No. WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlabel, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating the protein kinase targetin tissue samples, including human, and for identifying kinase ligandsby inhibition binding of a labeled compound. Accordingly, the presentinvention includes kinase enzyme assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofthe compounds of the invention. An “isotopically” or “radio-labeled”compound is a compound of the invention where one or more atoms arereplaced or substituted by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number typically found in nature(i.e., naturally occurring). Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ²H (also written as D for deuterium), ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. For example,for in vitro IDO enzyme labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the enzyme. Accordingly, the ability of atest compound to compete with the radio-labeled compound for binding tothe enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of diseases, such as cancer andother diseases referred to herein, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, or pharmaceuticallyacceptable salt thereof. Such kits can further include, if desired, oneor more of various conventional pharmaceutical kit components, such as,for example, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

The compounds of the Examples were found to be inhibitors of c-Metaccording to one or more of the assays provided herein.

EXAMPLES

Preparations for compounds of the invention are provided below. In someinstances, the crude product was a mixture of regioisomers. Typically,these isomers were separated on a preparative scale by HPLC or flashchromatography (silica gel) as indicated in the Examples. Typicalpreparative RP-HPLC column conditions were as follows

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: 0.1% TFA in acetonitrile; the flow rate was 30 ml/m, theseparating gradient was optimized for each compound using the CompoundSpecific Method Optimization protocol as described in literature[“Preparative LC-MS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem.,6, 874-883 (2004)].

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B: 0.15%NH₄OH in acetonitrile; the flow rate was 30 ml/m, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in literature [“PreparativeLC-MS Purification: Improved Compound Specific Method Optimization”, K.Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883(2004)].

The separated isomers were then typically subjected to analytical LC/MSfor purity check under the following conditions: Instrument; Agilent1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5 μm, 2.1×5.0 mm,Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: 0.025%TFA in acetonitrile; gradient 2% to 80% of B in 3 min with flow rate 1.5mL/min. Retention time (Rt) data in the Examples refer to theseanalytical LC/MS conditions unless otherwise specified.

Example 13-[1-(4-Methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazineand3-[1-(4-Methoxyphenyl)cyclopropyl]-7-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine

Step 1. Methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate

1-(4-Methoxyphenyl)cyclopropanecarboxylic acid (0.970 g, 5.05 mmol) indichloromethane (DCM; 5 mL) was mixed with oxalyl chloride (1.28 mL,15.1 mmol) followed by addition of a drop of N,N-dimethylformamide (DMF;20 μL). The mixture was stirred at room temperature (RT) for 2 h. Thesolvent was evaporated. The residue was co-evaporated with toluene (2×),and dissolved in DCM (10 mL). The solution was cooled at −10° C., andthen methanol (3 mL) was carefully added to the solution. The resultingmixture was allowed to warm to RT. The volatiles were evaporated underreduced pressure to afford the desired product (1.03 g, 99%).

Step 2. 1-(4-Methoxyphenyl)cyclopropanecarbohydrazide

A mixture of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (0.90 g,4.4 mmol) and hydrazine (0.65 mL, 21 mmol) was heated at 120° C. for 2h. After cooling, the excess hydrazine was removed under reducedpressure. The residue was treated with water, filtered and washed withwater to give the desired product (750 mg, 83%). Analytical LCMS:(M+H)⁺=207.1.

Step 3. 5-[1-(4-Methoxyphenyl)cyclopropyl]-1,3,4-oxadiazol-2-amine

Cyanogen bromide (0.424 g, 4.0 mmol) was added to an ice-cooled slurryof 1-(4-methoxyphenyl)cyclopropanecarbohydrazide (0.750 g, 3.64 mmol)and potassium bicarbonate (0.50 g, 5.0 mmol) in methanol (8 mL). Themixture was stirred at 0° C. for 1 h. the ice bath was allowed to warmslowly and stirred at RT for overnight. The reaction mixture was dilutedwith water (10 mL), stirred for 1 h. The precipitate was collected byfiltration and washed with water, and dried on high vacuum to afford thedesired product (600 mg, 71.3%). Analytical LCMS: (M+H)⁺=232.1.

Step 4. 5-[1-(4-Methoxyphenyl)cyclopropyl]-4H-1,2,4-triazole-3,4-diamine

A mixture of 5-[1-(4-methoxyphenyl)cyclopropyl]-1,3,4-oxadiazol-2-amine(0.60 g, 2.6 mmol), and hydrazine (0.64 mL, 20 mmol) in water (2.0 mL)was heated at 190° C. for 3 h. After cooling to RT, the mixture wasfurther cooled with ice-water. The crystalline solid formed wascollected by filtration, washed with water, and dried under high vacuumto yield the desired product (300 mg, 47.1%). Analytical LCMS:(M+H)⁺=246.1.

Step 5.3-[1-(4-methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazineand3-[1-(4-methoxyphenyl)cyclopropyl]-7-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine

A mixture of5-[1-(4-methoxyphenyl)cyclopropyl]-4H-1,2,4-triazole-3,4-diamine (70.2mg, 0.286 mmol) and oxo(phenyl)acetaldehyde hydrate (0.0435 g, 0.286mmol) in acetic acid (1.2 mL) was stirred at RT overnight. The mixturewas diluted with methanol (3.0 mL) and subject to preparative RP-HPLC toafford the two regioisomers.

Retention times for analytical LC/MS were as follows: Isomer-I: Rt=1.763min; Isomer-II: Rt=1.784 min. Analytical LCMS: (M+H)⁺=344.1.

Example 24-[1-(6-Phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]phenoland4-[1-(7-Phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]phenol

To a mixture of3-[1-(4-methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine(17.0 mg, 0.0495 mmol) and3-[1-(4-methoxyphenyl)cyclopropyl]-7-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine(17.0 mg, 0.0495 mmol) in DCM (3.0 mL) was added 1.00 M of borontribromide in DCM (0.5 mL). The mixture was stirred at RT for 3 h. Thesolvent was evaporated. The residue was diluted with methanol (5 mL).The resulting mixture was subject to preparative RP-HPLC to give the tworegioisomers. Analytical LCMS: (M+H)⁺=330.1. Isomer-I: Rt=1.451 min;Isomer-II: Rt=1.450 min.

Example 36-(4-Fluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(4-Fluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=362.1. Isomer-I: Rt=1.832min; Isomer-II: Rt=1.801 min.

Example 4 3-[1-(4-Methoxyphenyl)cyclopropyl]-6-(4-morpholin-4-ylphenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine and3-[1-(4-Methoxyphenyl)cyclopropyl]-7-(4-morpholin-4-ylphenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=399.1. Isomer-I: Rt=1.744min; Isomer-II: Rt=1.753 min.

Example 56-(4-Chlorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(4-Chlorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=378.0/380.1. Isomer-I:Rt=2.044 min; Isomer-II: Rt=2.012 min.

Example 64-3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylphenoland4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}phenol

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=360.1. Isomer-I: Rt=1.550min; Isomer-II: Rt=1.602 min.

Example 74-3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylbenzonitrileand4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}benzonitrile

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=369.1. Isomer-I: Rt=1.780min; Isomer-II: Rt=1.772 min.

Example 8N-(4-3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylphenyl)acetamideandN-(4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}phenyl)acetamide

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=401.1. Isomer-I: Rt=1.505min; Isomer-II: Rt=1.565 min.

Example 96-(4-Methoxyphenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(4-Methoxyphenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=374.1. Isomer-I: Rt=1.843min; Isomer-II: Rt=1.838 min.

Example 106-(2,4-Difluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(2,4-Difluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

These two compounds were prepared using procedures analogous to thosefor Example 1. Analytical LCMS: (M+H)⁺=380.1. Isomer-I: Rt=1.971 min;Isomer-II: Rt=1.989 min.

Example 116-(3,4-Dichlorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(3,4-Dichlorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=412.0/414.0. Isomer-I:Rt=2.261 min; Isomer-II: Rt=2.230 min.

Example 126-(3,4-Difluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(3,4-Difluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=380.1. Isomer-I: Rt=1.988min; Isomer-II: Rt=2.013 min.

Example 136-(3-Methoxyphenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(3-Methoxyphenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=374.1. Isomer-I: Rt=1.936min; isomer-II: Rt=1.941 min.

Example 146-(3-Bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(3-Bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=422.0/424.0. Isomer-I:Rt=2.054 min; isomer-II: Rt=2.036 min.

Example 156-(5-Bromo-2-thienyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(5-Bromo-2-thienyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=428.0/430.0.

Example 16 3-[1-(4-Methoxyphenyl)cyclopropyl]-6-(4-nitrophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine and3-[1-(4-Methoxyphenyl)cyclopropyl]-7-(4-nitrophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

Step 1. Ethyl hydrazinecarbimidothioate hydrobromide

A mixture of thiosemicarbazide (18.2 g, 0.200 mol) and ethyl bromide(32.0 g, 0.294 mol) in ethanol (250 mL) was heated under refluxovernight. The solvent was evaporated under reduced pressure. Theresidue was triturated with ether, filtered, and dried under high vacuumto afford the desired product (38 g, 95%). Analytical LCMS:(M+H)⁺=120.1.

Step 2. EthylN′-[1-(4-methoxyphenyl)cyclopropyl]carbonylhydrazonothio-carbamatehydrobromide

Oxalyl chloride (10.0 mL, 0.118 mol) was added to a solution of1-(4-methoxyphenyl)cyclopropanecarboxylic acid (8.10 g, 0.0421 mol) inmethylene chloride (50.0 mL), followed by the addition of DMF (0.1 mL).The mixture was stirred at RT for 2 h. The volatiles were evaporated.The residue was co-evaporated with toluene. The residue was dissolved intetrahydrofuran (160.0 mL), followed by the addition of ethylhydrazinecarbimidothioate hydrobromide (8.43 g, 0.0421 mol). The mixturewas stirred at RT overnight. The solvent was evaporated. The residue wastriturated with ether, filtered, and dried under high vacuum to give thedesired product (15 g, 95.1%). Analytical LCMS: (M+H)⁺=294.1.

Step 3. 5-[1-(4-Methoxyphenyl)cyclopropyl]-4H-1,2,4-triazole-3,4-diamine

A mixture of ethylN′-[1-(4-methoxyphenyl)-cyclopropyl]-carbonylhydrazonothio-carbamate(3.51 g, 0.012 mol) and hydrazine (3.0 mL, 0.0956 mol) in methanol (20.0mL) and water (20.0 mL) was heated under reflux overnight. The mixturewas diluted with methanol and water. The resulting solution was purifiedby RP-HPLC (pH=10.0 conditions) to give the desired product (1.23 g,41.9%). Analytical LCMS: (M+H)⁺=246.1.

Step 4.3-[1-(4-Methoxyphenyl)cyclopropyl]-6-(4-nitrophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazineand3-[1-(4-Methoxyphenyl)cyclopropyl]-7-(4-nitrophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

A mixture of5-[1-(4-methoxyphenyl)cyclopropyl]-4H-1,2,4-triazole-3,4-diamine (307mg, 1.25 mmol) and (4-nitrophenyl)(oxo)acetaldehyde hydrate (246 mg,1.25 mmol) in acetic acid (10.0 mL) was stirred at RT overnight. Themixture was concentrated under reduced pressure. The residue was flashchromatographed on a silica gel column with 5% methanol-DCM to affordtwo regioisomers.

Isomer-I (210 mg, 43%), TLC R_(f)=0.63 (plate: silica gel 60 F254, EMDChemicals Inc.; solvent: 10% methanol in DCM); Analytical LCMS:(M+H)⁺=389.1. Rt=1.962 min. ¹H-NMR (500 MHz, CDCl₃): 8.88 (s, 1H),8.40-8.48 (m, 2H), 8.36-8.39 (m, 2H), 7.39-7.43 (m, 2H), 6.79-6.83 (m,2H), 3.76 (s, 3H), 1.70-1.73 (m, 2H), 1.49-1.52 (m, 2H).

Isomer-II (200 mg, 41%), TLC R_(f)=0.47 (plate: silica gel 60 F254, EMDChemicals Inc.; solvent: 10% methanol in DCM); Analytical LCMS:(M+H)⁺=389.1. Rt=1.973 min. ¹H-NMR (500 MHz, CDCl₃): 8.96 (s, 1H),8.41-8.45 (m, 2H), 8.06-8.10 (m, 2H), 7.45-7.49 (m, 2H), 6.84-6.88 (m,2H), 3.78 (s, 3H), 1.75-1.79 (m, 2H), 1.52-1.55 (m, 2H).

Example 176-(4-Bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(4-Bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two compounds were prepared using procedures analogous tothose for Example 16. Analytical LCMS: (M+H)⁺=422.0/424.0. Isomer-I:Rt=2.138 min; Isomer-II: Rt=2.108 min.

Example 184-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}anilineand4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}aniline

Platinum (5.0 mg) on carbon (5%) was added to a 140 mg mixture of thetwo regioisomers:3-[1-(4-methoxyphenyl)cyclopropyl]-6-(4-nitrophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazineand3-[1-(4-methoxyphenyl)cyclopropyl]-7-(4-nitrophenyl)-[1,2,4]-triazolo[4,3-b][1,2,4]triazinein methanol (5.0 mL, 0.12 mol) under nitrogen. The mixture was stirredat RT under an atmosphere of hydrogen for 3 h, and was filtered. Thefiltrate was concentrated and subject to preparative RP-HPLC to affordtwo regioisomers. Analytical LCMS: (M+H)⁺=359.1. Isomer-I: Rt=1.565 min;Isomer-II: Rt=1.619 min.

Example 193-[1-(4-Methoxyphenyl)cyclopropyl]-6-[3-(1-methyl-1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand3-[1-(4-Methoxyphenyl)cyclopropyl]-7-[3-(1-methyl-1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

Sodium carbonate (19.1 mg, 0.180 mmol) in water (0.10 mL) was added to amixture of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(18.7 mg, 0.0900 mmol), tetrakis(triphenylphosphine)palladium(0) (2.0mg) and a 25.4 mg of a mixture of two regioisomers:6-(3-bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand7-(3-bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]-triazolo[4,3-b][1,2,4]triazinein ethanol (300 μL) and toluene (300 μL). The resulting mixture washeated at 150° C. for 1 h. After cooling, the mixture was concentratedand diluted with methanol. The resulting solution was filtered, and thefiltrate was subject to preparative RP-HPLC to give the tworegioisomers. Analytical LCMS: (M+H)⁺=424.1. Isomer-I: Rt=1.732 min;Isomer-II: Rt=1.764 min.

Example 203-[1-(4-Methoxyphenyl)cyclopropyl]-6-[3-(1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazineand3-[1-(4-Methoxyphenyl)cyclopropyl]-7-[3-(1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above two regioisomers were prepared using procedures analogous tothose for Example 19. Analytical LCMS: (M+H)⁺=410.1. Isomer-I: Rt=1.606min; Isomer-II: Rt=1.655 min.

Example 21 tert-Butyl(3′-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylbiphenyl-4-yl)carbamateand tert-Butyl(3′-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}biphenyl-4-yl)carbamate

The above two regioisomers were prepared using procedures analogous tothose for Example 19. Analytical LCMS: (M+H)⁺=535.1. Isomer-I: Rt=2.421min; Isomer-II: Rt=2.430 min.

Example 22 3-[1-(4-Methoxyphenyl)cyclopropyl]-(6 or7)-[4-(1H-pyrazol-4-yl)phenyl][1,2,4]-triazolo[4,3-b][1,2,4]triazine

Sodium carbonate (25.4 mg, 0.240 mmol) in water (0.10 mL) was added to amixture of Isomer-II from Example 17 (16.9 mg, 0.0400 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.6 mg,0.060 mmol) and tetrakis(triphenylphosphine)-palladium(0) (2.7 mg,0.0023 mmol) in ethanol (400 μL) and toluene (400 μL). The resultingmixture was heated at 150° C. for 2 h. The mixture was concentrated andthe residue diluted with methanol. The resulting solution was filteredand the filtrate was purified by preparative RP-HPLC to give the desiredproduct. Analytical LCMS: (M+H)⁺=410.1. Rt=1.622 min.

Example 23 3-[1-(4-Methoxyphenyl)cyclopropyl]-(6 or7)-[4-(1-methyl-1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

The above compound was prepared using procedures analogous to those forExample 22. Analytical LCMS: (M+H)⁺=424.2. Rt=1.766 min.

Example 243-[1-(4-Bromophenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine

Step 1. [(Aminocarbonyl)hydrazono] (phenyl)acetaldehyde

A mixture of 2,2-diethoxy-1-phenylethanone (6.25 g, 0.0300 mol) andsemicarbazide hydrochloride (3.34 g, 0.0300 mol) in ethanol-water (1:1v/v, 50 mL) was heated at 120° C. for 3 h. The mixture was concentratedunder reduced pressure. The residue was treated with methanol, filtered,and washed with methanol to give the desired product (3.40 g, 59.3%).Analytical LCMS: (M+H)⁺=192.1. ¹H-NMR (400 MHz, DMSO-D₆): δ 11.03 (s,1H), 7.97-8.01 (m, 2H), 7.61-7.67 (m, 1H), 7.50-7.56 (m, 2H), 7.34 (b,1H), 6.54 (b, 2H).

Step 2. 6-Phenyl-1,2,4-triazin-3(2H)-one

[(Aminocarbonyl)hydrazono](phenyl)acetaldehyde (3.00 g, 0.0157 mol) inacetic acid (15.0 mL) was heated at 130° C. for 6 h. After cooling, thesolvent was removed under reduced pressure. The residue was trituratedwith ether, filtered, washed with ether, and dried under high vacuum togive the desired product (2.45 g, 90.1%). Analytical LCMS: (M+H)⁺=174.0.

Step 3. 3-Chloro-6-phenyl-1,2,4-triazine

A mixture of 6-phenyl-1,2,4-triazin-3(2H)-one (2.45 g, 0.0141 mol) andDMF (0.5 mL) in phosphoryl chloride (20.0 mL, 0.214 mol) and chloroform(20.0 mL) was heated under reflux overnight. After cooling, thevolatiles were removed under reduced pressure. The residue was dissolvedin DCM (60 mL) and was poured into ice with stirring. The mixture wasneutralized with NaOH (1N), and filtered through a pad of celite toremove a small amount of insoluble residue. The organic layer wasseparated. The aqueous layer was extracted with DCM (3×20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was flash chromatographed on a silica gelcolumn to give the desired product (2.20 g, 81.1%). Analytical LCMS:(M+H)⁺=192.1/194.1.

Step 4. 3-Hydrazino-6-phenyl-1,2,4-triazine

Hydrazine hydrate (1.50 mL, 0.0308 mol) was added to suspension of3-chloro-6-phenyl-1,2,4-triazine (2.20 g, 0.0115 mol) in pyridine (12.0mL) at 0° C. and stirred at 0° C. until a precipitate formed. Themixture was then heated at 65° C. for 30 min. The solvent was evaporatedunder reduced pressure. The residue was triturated with water, filtered,and washed with water. The crystalline formed was collected and driedunder high vacuum to give the desired product (2.0 g, 93%). AnalyticalLCMS: (M+H)⁺=188.1.

Step 5.3-[1-(4-Bromophenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine

A mixture of 3-hydrazino-6-phenyl-1,2,4-triazine (18.7 mg, 0.10 mmol)and 1-(4-bromophenyl)cyclopropanecarboxylic acid (24.1 mg, 0.10 mmol) inphosphoryl chloride (0.50 mL) was heated at 120° C. for 3 h. Excessphosphoryl chloride was removed under reduced pressure. The residue wastreated with water and methanol. The resulting solution was subject topreparative RP-HPLC (pH=2) to give the desired product as a TFA salt.Analytical LCMS: (M+H)⁺=392.0/394.0

Example 253-[1-(3-Bromophenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 24. Analytical LCMS: (M+H)⁺=392.0/394.0.

Example 263-[1-(4-Methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 24. Analytical LCMS: (M+H)⁺=344.1.

Example 276-[1-(6-Phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]quinoline

This compound was prepared using procedures analogous to those forExample 24. Analytical LCMS: (M+H)⁺=365.1.

Example 28 3-[1-(4-Chlorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

Step 1. 2,2-Diethoxy-1-(4-fluorophenyl)ethanone

A mixture of 1-(4-fluorophenyl)-2,2-dihydroxyethanone (4.0 g, 0.024mol), ethyl orthoformate (7.3 g, 0.049 mol), p-toluenesulfonic acidmonohydrate (0.2 g, 0.001 mol) in methylene chloride (50 mL) was heatedat reflux for 40 min. After cooling, the mixture was concentrated. Theresidue was flash chromatographed on a silica gel column eluting withDCM to give 5.15 g of the desired product. ¹H-NMR (300 MHz, CDCl₃):8.18-8.25 (m, 2H), 7.08-7.16 (m, 2H), 5.18 (s, 1H), 3.58-3.82 (m, 4H),1.25 (t, J=7.0 Hz, 6H).

Step 2. 6-(4-Fluorophenyl)-1,2,4-triazin-3(2H)-one

A mixture of 2,2-diethoxy-1-(4-fluorophenyl)ethanone (5.15 g, 0.0228mol), semicarbazide hydrochloride (2.6 g, 0.024 mol) in ethanol (50 mL)was stirred at RT overnight, and then heated at 80° C. for 5 h. Themixture was concentrated. The residue was dissolved in acetic acid (50mL), and heated at 130° C. for 6 h. After cooling, the mixture wasconcentrated, and the residue was triturated with ethyl ether, filtered,and washed with ether and then hexane. The crystalline solid wascollected and dried under high vacuum to the desired product (4.18 g,96.1%). Analytical LCMS: (M+H)⁺=192.1.

Step 3. 6-(4-Fluorophenyl)-3-hydrazino-1,2,4-triazine

Hydrazine hydrate (0.28 mL, 0.0057 mol) was added to a suspension of3-chloro-6-(4-fluorophenyl)-1,2,4-triazine (400 mg, 0.002 mol) inpyridine (4 mL) at 0° C. and stirred at 0° C. until a precipitateformed. The mixture was then heated at 65° C. for 30 min. The solventwas evaporated under reduced pressure. The residue was triturated withwater, filtered, and washed with water. The crystalline solid wascollected and dried under high vacuum to give the desired product (360mg, 91.9%). Analytical LCMS: (M+H)⁺=206.1.

Step 4.3-[1-(4-Chlorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

A mixture of 6-(4-fluorophenyl)-3-hydrazino-1,2,4-triazine (20.5 mg,0.10 mmol) and 1-(4-chlorophenyl)cyclopropanecarboxylic acid (19.6 mg,0.10 mmol) in phosphoryl chloride (0.50 mL) was heated at 120° C. for 3h. Excess phosphoryl chloride was removed under reduced pressure. Theresidue was treated with water and methanol. The resulting solution wassubject to RP-HPLC (pH=2) to give the desired product as a TFA salt.Analytical LCMS: (M+H)⁺=366.0.

Example 29 3-[1-(2,4-Dichlorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=400.0.

Example 30 3-[1-(3-Bromophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=409.9/411.9.

Example 31 3-[1-(4-Bromophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=409.9/411.9.

Example 32 3-[1-(2-Chlorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=366.1.

Example 336-(4-Fluorophenyl)-3-[1-(2-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=362.0.

Example 346-(4-Fluorophenyl)-3-[1-(3-fluorophenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=350.0.

Example 356-(4-Fluorophenyl)-3-{1-[3-(trifluoromethyl)phenyl]cyclopropyl}[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=400.0.

Example 363-[1-(2-Chloro-6-fluorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=384.0.

Example 37 3-[1-(1,3-Benzodioxol-5-yl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=376.1.

Example 38 4-{1-[6-(4-Fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=383.0.

Example 39 6-{1-[6-(4-Fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=383.0.

Example 40 6-{1-[6-(3-Bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=443.0/445.0.

Example 41 6-{1-[6-(4-Bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline

This compound was prepared as a TFA salt using procedures analogous tothose for Example 28. Analytical LCMS: (M+H)⁺=443.0/445.0.

Example 42 3-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzonitrile

A mixture of6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(Example 40, 10 mg, 0.02 mmol), zinc cyanide (3.24 mg, 0.0271 mmol),bis(tri-t-butylphosphine)palladium (7 mg, 0.01 mmol), and zinc powder(1.77 mg, 0.0271 mmol) in DMF (0.6 mL) was heated at 170° C. for 20 minunder microwave. After cooling to ambient temperature, the mixture wasfiltered. The filtrate was diluted with methanol and subject topreparative RP-HPLC (pH=10) to afford the desired product. AnalyticalLCMS: (M+H)⁺=390.2.

Example 43 4-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzonitrile

This compound was prepared using procedures analogous to those forExample 42. Analytical LCMS: (M+H)⁺=390.2.

Example 443-[1-(4-Methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-amine

Step 1. 3-(Methylthio)-6-phenyl-1,2,4-triazin-5(4H)-one

A mixture of thiosemicarbazide (1.8 g, 0.020 mol) and benzoylformic acid(3.0 g, 0.020 mol) in water (50 mL) was heated under reflux for 15 min.Then potassium hydroxide (1.5 g, 0.027 mol) in methanol (50 mL) wasadded at 80° C. The reaction mixture was stirred and heated at 80° C.for 2 days. After cooling to 35° C., methyl iodide (1.4 mL, 0.022 mol)was added. The reaction mixture was stirred at 40° C. for 30 min. Themixture was concentrated. The precipitate formed was collected byfiltration, washed with water, and dried under vacuum to afford thedesired product (4.3 g, 97.7%). Analytical LCMS: (M+H)⁺=220.1.

Step 2. 3-Hydrazino-6-phenyl-1,2,4-triazin-5(4H)-one

To 3-(methylthio)-6-phenyl-1,2,4-triazin-5(4H)-one (4.3 g) in isopropylalcohol (40 mL) was added hydrazine (6.41 g, 0.200 mol). The reactionmixture was refluxed for 10 h. After cooling, the crystalline solidformed was filtered and washed with isopropyl alcohol. The crystallinesolid was collected and dried in vacuo to afford the desired product.Analytical LCMS: (M+H)⁺=204.1.

Step 3.3-[1-(4-Methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-7(8H)-one

To a solution of 3-hydrazino-6-phenyl-1,2,4-triazin-5(4H)-one (40.0 mg,0.197 mmol) in pyridine (0.5 mL) was added1-(4-methoxyphenyl)cyclopropanecarbonyl chloride (0.062 g, 0.30 mmol)and the resulting mixture was irradiated under microwave at 150° C. for15 min. The reaction mixture was diluted with methanol and purified byRP-HPLC to afford the desired product (50 mg, 70%). Analytical LCMS:(M+H)⁺=360.2.

Step 4.3-[1-(4-Methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-amine

A mixture of3-[1-(4-methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-7(8H)-one(43.1 mg, 0.120 mmol) and phosphoryl chloride (1.0 mL, 0.011 mol) wasstirred and heated at 120° C. for 4 h. Excess phosphoryl chloride wasremoved under reduced pressure. The residue was dissolved inacetonitrile (0.5 mL). To the solution was added ammonium hydroxide(20.0 μL). The mixture was stirred at RT for 30 min, and was dilutedwith methanol. The resulting solution was subject to preparative RP-HPLC(pH=10) to give the desired product. Analytical LCMS: (M+H)⁺=359.1.

Example 456-(4-Fluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-amine

Step 1. Methyl (4-fluorophenyl)(oxo)acetate

A mixture of 4-fluorobenzoyl chloride (3 g, 0.02 mol) and copper cyanide(2.3 g, 0.026 mol) in acetonitrile (2 mL) and in toluene (4 mL) washeated under reflux for 3 h. After cooling, the mixture was filtered.The filtrate was diluted with ethyl acetate, washed with water, brine,and dried over MgSO₄. The mixture was filtered and concentrated. Theresidue was dissolved in ether-methanol. The solution was saturated withhydrogen chloride gas, and stirred at RT for 2 h. The precipitate formedwas collected by filtration, washed with ether, and dried under highvacuum to give the desired product (2.1 g, 61%). ¹H-NMR (300 MHz,CDCl₃): 8.06-8.13 (m, 2H), 7.15-7.23 (m, 2H), 3.98 (s, 3H).

Step 2. 6-(4-Fluorophenyl)-3-(methylthio)-1,2,4-triazin-5(4H)-one

A mixture of methyl (4-fluorophenyl)(oxo)acetate (1.1 g, 0.0059 mol),thiosemicarbazide (0.54 g, 0.0059 mol) in water (10 mL) was heated atreflux for 15 min. Then methanol (10 mL) was added, followed bypotassium hydroxide (0.43 g, 0.0077 mol). The mixture was stirred at 90°C. overnight. After cooling, methyl iodide (4 mL, 0.06 mol) was added.The mixture was stirred at RT for 30 min. The precipitate formed wascollected by filtration, washed with ether, and dried under high vacuumto give the desired product (1.2 g, 77%). Analytical LCMS: (M+H)⁺=238.1.

Step 3.6-(4-Fluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-amine

This compound was prepared using procedures analogous to Steps 2-4 ofExample 44. Analytical LCMS: (M+H)⁺=377.1.

Example 466-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-1,3-benzothiazol-2-amine

4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}aniline(preparation in Example 18, isomer-I, 35.8 mg, 0.10 mmol) was dissolvedin acetic acid (1.00 mL). To the solution was added potassiumthiocyanate (38.8 mg, 0.400 mmol) and bromine (5.14 μL, 0.10 mmol) inacetic acid (0.10 mL). The mixture was stirred at RT overnight, and wasdiluted with DMSO (1.0 mL). The resulting solution was purified byRP-HPLC (pH=2) to give the desired product as a TFA salt. AnalyticalLCMS: (M+H)⁺=416.0.

Example 471-(4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}phenyl)pyrrolidin-2-one

A mixture of6-(4-bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]-triazolo[4,3-b][1,2,4]triazine(Example 17, isomer-I, 25.3 mg, 0.0600 mmol), 2-Pyrrolidinone (5.47 μL,0.0720 mmol), (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (1.9 μL,0.012 mmol), copper(I) iodide (1.14 mg, 0.00600 mmol), and potassiumcarbonate (17.4 mg, 0.126 mmol) in 1,4-dioxane (0.75 mL) was cooled(dry-ice acetone bath), purged in vacuo, and charged with nitrogen. Thenthe mixture was heated at 150° C. for 4 h. After cooling, the mixturewas diluted with methanol. The resulting solution was purified byRP-HPLC (pH=10) to give the desired product. Analytical LCMS:(M+H)⁺=427.1.

Example 48N-Cyclopropyl-4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzamide

Step 1. 4-(dihydroxyacetyl)benzoic acid

To a solution of 4-acetylbenzoic acid (4.3 g, 0.026 mol) in dimethylsulfoxide (60 mL) was added slowly an aqueous solution of hydrogenbromide (48%, 8.9 mL) at RT with stirring. Then the mixture was heatedat 60° C. overnight. After cooling, the mixture was diluted withice-water. The precipitate formed was collected by filtration, washedwith water, and dried in-vacuo to afford the desired product (4.65 g,91.1%) which was directly used in next reaction step without furtherpurification.

Step 2.4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoicacid

A mixture of 4-(dihydroxyacetyl)benzoic acid hydrate (0.350 g, 1.63mmol) and5-[1-(4-methoxyphenyl)cyclopropyl]-4H-1,2,4-triazole-3,4-diamine (0.245g, 1.00 mmol, prepared as in Example 16, Steps 1-3) in acetic acid (5.00mL) was stirred at RT overnight. The solvent was evaporated. The residuewas purified by RP-HPLC (pH=10) to give the desired product (isomer I:33 mg, Rt=1.672 min) and4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}benzoicacid (isomer JJ: 166 mg, Rt=1.747 min.). Analytical LCMS: (M+H)⁺=388.3.

Step 3.N-cyclopropyl-4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]-triazin-6-yl}benzamide

A mixture of4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoicacid (isomer-I from step 2, 14.0 mg, 0.0361 mmol), cyclopropylamine(3.76 μL, 0.0542 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(16.0 mg, 0.0361 mmol) and N,N-diisopropylethylamine (25.2 μL, 0.145mmol) in DMF (1.0 mL) was stirred at RT for 3 h. The mixture was dilutedwith methanol and purified by RP-HPLC (pH=10) to give the desiredproduct. Analytical LCMS: (M+H)⁺=427.3.

Example 494-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-(tetrahydro-2H-pyran-4-yl)benzamide

This compound was prepared using procedures analogous to those forExample 48. Analytical LCMS: (M+H)⁺=471.4.

Example 50N-(trans-4-Hydroxycyclohexyl)-4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzamide

This compound was prepared using procedures analogous to those forExample 48. Analytical LCMS: (M+H)⁺=485.4.

Example 51 Ethyl4-[(4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]piperidine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 48. Analytical LCMS: (M+H)⁺=542.3.

Example 524-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-(pyridin-2-ylmethyl)benzamide

This compound was prepared using procedures analogous to those forExample 48. Analytical LCMS: (M+H)⁺=478.3.

Example 53 Ethyl1-[(4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]cyclopropanecarboxylate

This compound was prepared using procedures analogous to those forExample 48. Analytical LCMS: (M+H)⁺=499.4.

Example 54N-[1-(6-Fluoropyridin-2-yl)pyrrolidin-3-yl]-4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzamide

This compound was prepared using procedures analogous to those forExample 48. Analytical LCMS: (M+H)⁺=551.0.

Example 554-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl-N′-pyridin-2-yl}benzohydrazide

This compound was prepared using procedures analogous to those forExample 48. Analytical LCMS: (M+H)⁺=479.2.

Example 566-(1-{6-[3-(1H-imidazol-1-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline

To a solution of6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(20 mg, 0.04 mmol) in 1,4-dioxane (1 mL) was added 1H-imidazole (4.61mg, 0.0677 mmol), sodium iodide (14 mg, 0.090 mmol),(1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (1 mg, 0.009 mmol),copper(I) iodide (0.8 mg, 0.004 mmol), and cesium carbonate (31 mg,0.095 mmol), then the mixture was heated at 120° C. overnight. Thereaction mixture was cooled to RT and filtered. The filtrate was dilutedwith MeOH and purified by RP-HPLC (pH=10) to afford the desired compound8 mg (40%) LCMS: (M+H)+=431.1.

Example 576-(1-{6-[4-(1H-imidazol-1-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline

This compound was prepared by using procedures analogous to those forExample 56. Analytical LCMS: (M+H)+=431.1

Example 58 3-{4-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1,3-oxazolidin-2-one

This compound was prepared using procedures analogous to those forExample 56. Analytical LCMS: (M+H)+=450.1

Example 596-(1-{6-[3-(6-Methoxypyridin-3-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline

To a mixture of6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(16 mg, 0.036 mmol),2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10mg, 0.043 mmol), and potassium phosphate (30 mg, 0.14 mmol) in1,4-dioxane (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0)(3 mg) and water (0.1 mL). The resulting mixture was heated at 120° C.overnight. The reaction mixture was cooled to RT and concentrated. Theresidue was dissolved in MeOH and purified by RP-HPLC (pH=10) to affordthe desired compound 10 mg (60%). Analytical LCMS: (M+H)⁺=472.2.

Example 60 N,N-Dimethyl-5-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridine-2-carboxamide

This compound was prepared using procedures analogous to those forExample 59. Analytical LCMS: (M+H)+=513.3.

Example 61 N-Ethyl-5-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridine-2-carboxamide

This compound was prepared using procedures analogous to those forExample 59. Analytical LCMS: (M+H)+=513.3

Example 62 N-Methyl-2-(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide

Step 1. Tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g,0.0077 mol) in DMF (25 mL) was added 2-bromoacetic acid1,1-dimethylethyl ester (1.2 mL, 0.0085 mol) and cesium carbonate (3.8g, 0.012 mol). The suspension was stirred at 90° C. overnight. Thereaction mixture was cooled to RT and partitioned with ethyl acetate andwater. The organic layer was washed with water, brine, and dried overMgSO₄. The solution was concentrated to afford the desired compound (2.0g, 84%). Analytical LC/MS: (M+H)⁺=309.4.

Step 2. Tert-butyl(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetate

This compound was prepared using procedures analogous to those forExample 59. Analytical LCMS: (M+H)⁺=545.2.

Step 3.N-Methyl-2-(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide

To a solution of tert-butyl(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetate(11 mg, 0.020 mmol) in DCM (2 mL) was added TFA (1 mL). The solution wasstirred at RT for 2 h. The volatiles were evaporated under reducedpressure. The residue was co-evaporated with toluene three times.

The above residue was dissolved in DMF (0.5 mL), to this solution wasadded benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (10.7 mg, 0.0242 mmol), 2.0 M of methylamine intetrahydrofuran (20 μL) and N,N-diisopropylethylamine (7.0 μL, 0.040mmol). The mixture was stirred at RT for 3 h, diluted with methanol, andpurified by RP-HPLC (pH=2) to afford the desired compound as a TFA salt.Analytical LCMS: (M+H)+=502.2

Example 63 2-(4-{3-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=558.2.

Example 64N-(1-Pyridin-2-ylethyl)-2-(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=593.2.

Example 65 N,N-Dimethyl-2-(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide

This compound was prepared using procedures analogous to those forExample 62. Analytical LCMS: (M+H)⁺=516.1.

Example 66 N-Methyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=502.1.

Example 67 N-Isopropyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=530.2.

Example 68 N-(Cyclopropylmethyl)-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=542.0.

Example 69 N-Isopropyl-2-methyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)propanamide

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=558.2

Example 706-[1-(6-{4-[1-(1,1-Dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]phenyl}[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]quinoline

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=570.2.

Example 71 (2R)—N,N-Dimethyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)propanamide

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=530.1.

Example 72 (2S)—N,N-Dimethyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)propanamide

This compound was prepared as a TFA salt using procedures analogous tothose for Example 62. Analytical LCMS: (M+H)⁺=530.2.

Example 736-(3-Bromophenyl)-3-[1-(3-methyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

Step 1. (6-Chloropyridin-3-yl)acetonitrile

To a solution of 2-chloro-5-(chloromethyl)pyridine (5.0 g, 0.031 mol) inethanol (38 mL) and water (19 mL) was added potassium cyanide (2.41 g,0.0370 mol) at RT under nitrogen atmosphere. The reaction mixture wasstirred at 50° C. overnight. The reaction was diluted with water andextracted with DCM. The organic layer was washed with brine and driedover sodium sulfate. The solution was filtered and the filtrate wasconcentrated to afford the desired compound (4.2 g, 89%). AnalyticalLCMS: (M+H)⁺=153.1.

Step 2. 1-(6-Chloropyridin-3-yl)cyclopropanecarboxylic acid

To a stirred mixture of (6-chloropyridin-3-yl)acetonitrile (2.00 g,0.0131 mol), benzyltriethylammonium chloride (0.2 g, 0.0008 mol), and1-bromo-2-chloroethane (3.26 mL, 0.0393 mol), was added sodium hydroxideaqueous solution (50%, 3 mL, 0.08 mol) drop-wise at 50° C. The mixturewas stirred at 50° C. for 5 h. 1,2-ethanediol (4 mL) was added to theabove mixture and stirred at 100° C. overnight. The aqueous layer wasacidified to pH ˜1, and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried with sodium sulfate, filtered,and concentrated to afford the desired compound (2.2 g, 85%). AnalyticalLCMS: (M+H)⁺=198.0.

Step 3. Methyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate

A mixture of 1-(6-chloropyridin-3-yl)cyclopropanecarboxylic acid (2.0 g,0.010 mol) and sulfuric acid (0.42 mL, 0.0079 mol) in methanol (30 mL)was stirred at 80° C. for 6 h. The mixture was cooled to RT andconcentrated. The residue was dissolved in saturated sodium bicarbonateand extracted with ethyl acetate. The organic layers were washed withbrine, dried with Na₂SO₄, filtered, and concentrated under reducedpressure to give a crude product (2.0 g, 93%). Analytical LCMS:(M+H)⁺=212.0.

Step 4. Methyl 1-(6-hydrazinopyridin-3-yl)cyclopropanecarboxylate

To a solution of methyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate(1 g, 0.005 mol) in pyridine (2 mL) was added hydrazine (0.30 mL, 0.0094mol). The solution was heated at 90° C. overnight. The reaction solutionwas cooled to RT, and then diluted with a small amount of ice-water. Theprecipitate was collected by filtration, and dried under vacuum toafford the desired compound (0.9 g, 90%). Analytical LCMS: (M+H)⁺=208.0.

Step 5.1-(3-Methyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)cyclopropanecarboxylicacid

To a solution of methyl1-(6-hydrazinopyridin-3-yl)cyclopropanecarboxylate (150 mg, 0.72 mol) inethanol (3 mL) was added acetaldehyde (33.5 mg, 0.760 mmol) and aceticacid (41 μL, 0.72 mmol). The mixture was stirred at RT for 2 h, and thenconcentrated to dryness. The residue was dissolved in methylene chloride(3 mL), and iodobenzene diacetate (256 mg, 0.796 mmol) was addeddropwise. The reaction mixture was stirred at RT overnight. The reactionsolution was concentrated to dryness. The residue was purified throughsilica gel chromatograph using 10% MeOH in CH₂Cl₂ to afford the desiredcompound (50 mg, 30%). Analytical LCMS: (M+H)⁺=218.0.

Step 6.6-(3-Bromophenyl)-3-[1-(3-methyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine

This compound was prepared as a TFA salt using procedures analogous tothose for Example 1. Analytical LCMS: (M+H)⁺=447.0.

Example 74 6-{1-[6-(4-Bromo-3-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline

Step 1. 4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide

Oxalyl chloride (38.1 mL, 0.450 mol) was slowly added to a mixture of4-bromo-3-fluorobenzoic acid (49.3 g, 0.225 mol) in methylene chloride(300 mL), then DMF (1.0 mL) was added and the reaction was stirred at RTfor 2 h. The volatiles were removed under reduced pressure andco-evaporated with toluene for 3 times. The residue was then dissolvedin methylene chloride (100 mL). The solution was added dropwise to amixture of N,O-dimethyl-hydroxylamine hydrochloride (30.7 g, 0.315 mol)and potassium carbonate (120 g, 0.90 mol) in methylene chloride (300 mL)and water (300 mL). The reaction was stirred at RT for 2 h. The organiclayer was separated. The aqueous layer was extracted with methylenechloride (2×50 mL). The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated under reduced pressure togive the product (58.5 g, 99%). Analytical LCMS: (M+H)⁺=261.9/263.9.

Step 2. 1-(4-Bromo-3-fluorophenyl)ethanone

To a solution of 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (58.5 g,0.223 mol) in tetrahydrofuran (500 mL) was added 3.00 M ofmethylmagnesium chloride in tetrahydrofuran (125 mL, 0.38 mol) at 0° C.The mixture was stirred for 1 h at 0° C., and was quenched with coldsaturated NH₄Cl solution (150 mL). The organic layer was separated andconcentrated under reduced pressure. The residue was diluted with ethylacetate (100 mL). The aqueous layer was diluted with water (100 mL) andwas extract with ethyl acetate (3×50 mL). The organic solution andextracts were combined, washed with brine, dried over MgSO₄, filtered,and concentrated under reduced pressure to give product (48.4 g, 99%)which was directly used in next step without further purification.

Step 3. 1-(4-bromo-3-fluorophenyl)-2,2-dihydroxyethanone

To a solution of 1-(4-bromo-3-fluorophenyl)ethanone (9.0 g, 0.041 mol)in dimethyl sulfoxide (40 mL) was added slowly 48% of hydrogen bromideaqueous solution (14 mL). The reaction was stirred at 60° C. overnightand then cooled to RT, poured into ice-water, the precipitate wasfiltered and washed with water, and the solid was dried under vacuumovernight (8.1 g was obtained). The aqueous portion was extracted withethyl acetate three times. The combined extracts were washed with waterand brine, dried, filtered, and concentrated to give an additional 2.2 gof the product.

Step 4. 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone

To a solution of 1-(4-bromo-3-fluorophenyl)-2,2-dihydroxyethanone (3.5g, 0.014 mol) in toluene (30 mL) was added ethyl orthoformate (5.8 mL,0.035 mol) and p-toluenesulfonic acid (100 mg). The reaction wasrefluxed for 4 h. After cooled to RT, the mixture was diluted with ethylacetate, washed with saturated NaHCO₃ solution, water, and brine, driedover MgSO₄, filtered and concentrated to give the product (4.0 g, 93%)which was used in the next step without further purification.

Step 5. 6-(4-bromo-3-fluorophenyl)-3-(methylthio)-1,2,4-triazine

A solution of 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (2.24 g,0.00734 mol), thiosemicarbazide (0.702 g, 0.00771 mol), andp-toluenesulfonic acid monohydrate (70 mg) in ethanol (50 mL) was heatedat 90° C. for 2 h. LCMS showed that the starting material was consumed.After cooled to RT, to the mixture was added methyl iodide (2.3 mL,0.037 mol). The mixture was stirred at RT for 2 h, and concentrated. Tothe residue was added acetic acid (15 mL). The mixture was heated at 60°C. for 4 h. The volatiles were evaporated under reduced pressure. Theresidue was treated with methanol. The formed precipitate was collectedby filtration, and dried in-vacuo to afford the desired product (1.15 g,51%) which was directly used in next step without further purification.

Step 6. 6-(4-bromo-3-fluorophenyl)-3-hydrazino-1,2,4-triazine

A mixture of 6-(4-bromo-3-fluorophenyl)-3-(methylthio)-1,2,4-triazine(1.15 g, 0.00383 mol) and hydrazine hydrate (0.74 mL, 0.015 mol) inethanol (50 mL) was heated at 90° C. for 20 h. After cooling, the formedprecipitate was collected by filtration, and dried in-vacuo to affordthe desired product (0.845 g, 77.6%).

Step 7. quinolin-6-ylacetonitrile

To a mixture of(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.7 g, 0.012mol), tris(dibenzylideneacetone)dipalladium(0) (10.0 g, 0.012 mol),6-bromoquinoline (120.0 g, 0.577 mol) in DMF (360 mL) in a 3-neck roundbottom flask with stirring under an atmosphere of nitrogen was added(trimethylsilyl)acetonitrile (98.7 mL, 0.721 mol), followed by zincdifluoride (42 g, 0.40 mol). The flask was sealed under an atmosphere ofnitrogen. The reaction was stirred at 105° C. for 20 h. After coolingthe solution to RT, the reaction mixture was quenched with aqueousammonia solution and extracted with ethyl acetate (3×500 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column (ethyl acetate in hexanes:0-65%) to afford the desired product quinolin-6-ylacetonitrile (70 g,72.1%). Analytical LCMS: (M+H)⁺=168.9.

Step 8. 1-quinolin-6-ylcyclopropanecarbonitrile

60 mL of 50% aqueous NaOH was added to a mixture of1-bromo-2-chloroethane (22.0 mL, 0.265 mol), quinolin-6-ylacetonitrile(16.0 g, 0.0666 mol), and benzyltriethylammonium chloride (0.99 g,0.0043 mol) at 50° C. The mixture was stirred at 50° C. for 3 h. Aftercooling to RT, the reaction mixture was poured into 100 ml of water, andextracted with DCM (3×100 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered through a pad of silica gel and washedwith ethyl acetate in DCM (20%). The filtrate was concentrated to givethe crude product 1-quinolin-6-ylcyclopropanecarbonitrile (12.4 g, 96%)which was directly used in the next step without further purification.

Step 9. 1-quinolin-6-ylcyclopropanecarbaldehyde

Diisobutylaluminum hydride in THF (1.0 M, 96 mL, 0.096 mol) was added toa solution of 1-quinolin-6-ylcyclopropanecarbonitrile (12.4 g, 0.0639mol) in toluene (120 mL) at −78° C. under an atmosphere of nitrogen. Thereaction mixture was allowed to warm to −5 to 0° C., and stirred at thattemperature for 3 h. The mixture was re-cooled to −60° C. Isopropylalcohol (10 mL) was carefully added dropwise. After stirring for 30 min,the mixture was warmed to −5 to 0° C. The mixture was diluted with ethylacetate, quenched with water and extracted with ethyl acetate. Thecombined organic layers were washed with water and brine, dried overanhydrous Na₂SO₄, filtered through a pad of silica gel and washed withethyl acetate in hexanes (40%). The filtrate was concentrated to yieldthe desired 1-quinolin-6-ylcyclopropanecarbaldehyde (12 g, 95.1%).

Step 10.6-1-[6-(4-bromo-3-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropylquinoline

A mixture of 6-(4-bromo-3-fluorophenyl)-3-hydrazino-1,2,4-triazine (0.50g, 0.0018 mol), 1-quinolin-6-ylcyclopropanecarbaldehyde (0.35 g, 0.0018mol) in a solution of ethanol (10 mL) and acetic acid (2 mL) was stirredat RT for 4 h. The mixture was concentrated. The residue was suspendedin methylene chloride (20 mL). To the suspension was added iodobenzenediacetate (0.62 g, 0.0019 mol) with stirring at RT. The mixture wasstirred at RT overnight and concentrated. The residue was purified byflash chromatography on a silica gel column to afford the desiredproduct (579 mg, 71.3%). Analytical LCMS: (M+H)⁺=460.9/462.9.

Example 756-(1-{6-[3-Fluoro-4-(1H-imidazol-1-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline

To a solution of6-1-[6-(4-bromo-3-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropylquinoline(20 mg) in 1,4-dioxane (1 mL) was added 1H-imidazole (4.61 mg), sodiumiodide (14 mg), (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (1 mg),copper(I) iodide (0.8 mg), and cesium carbonate (31 mg). The mixture washeated at 120° C. overnight. The reaction mixture was cooled to RT andfiltered. The filtrate was diluted with methanol and purified by RP-HPLC(pH=10) to afford the desired compound. Analytical LCMS: (M+H)⁺=449.1.

Example 76 5-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-N,N-dimethylpyridine-2-carboxamide

To a mixture of6-1-[6-(4-bromo-3-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropylquinoline(20 mg, 0.04 mmol), 6-[(dimethylamino)carbonyl]pyridin-3-ylboronic acid(13 mg, 0.065 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL), wasadded tetrakis(triphenylphosphine)palladium(0) (3 mg) and potassiumphosphate (28 mg). The resulting mixture was heated at 120° C.overnight. The reaction mixture was cooled to RT and concentrated. Theresidue was dissolved in MeOH and purified by RP-HPLC (pH=10) to affordthe desired compound. Analytical LCMS: (M+H)⁺=531.1

Example 77 5-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridin-2-amine

This compound was prepared using procedures analogous to those forExample 76. Analytical LCMS: (M+H)⁺=475.0

Example 78 Methyl(5-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridin-2-yl)carbamate

To a solution of5-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridin-2-amine(20.0 mg, 0.0422 mmol) (Example 77) in DMF (1 mL) was added methylchloroformate (3.25 μL, 0.0421 mmol) and N,N-diisopropylethylamine (15μL, 0.084 mmol). The solution was stirred at RT overnight. The reactionsolution was diluted with methanol and purified by RP-HPLC (pH=2) toafford the desired compound as a TFA salt (7 mg, 30%). Analytical LCMS:(M+H)⁺=533.1

Example 79 3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl]-6-(4-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

Step 1. 1,3-Benzothiazol-6-ylmethyl methanesulfonate

1,3-benzothiazol-6-ylmethanol (1.56 g, 0.00944 mol) andN,N-diisopropylethylamine (2.47 mL, 0.0142 mol) were stirred inmethylene chloride (16 mL). The reaction mixture was cooled in anethylene glycol/water (4/1)/dry ice bath. To the solution was addeddropwise a solution of methanesulfonyl chloride (1.10 mL, 0.0142 mol) inDCM (2 mL). After 30 min the reaction mixture was quenched by addingwater, and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to give the desired product which was directlyused in the next step without purification. LCMC: (M+H)⁺=244.2.

Step 2. 1,3-Benzothiazol-6-ylacetonitrile

A solution of potassium cyanide (0.68 g, 0.010 mol) in water (3.0 mL)was added under nitrogen to a cooled (with an ethylene glycol/water(4/1)/dry ice bath) solution of 1,3-benzothiazol-6-ylmethanol in DMF (30mL). The reaction mixture was warmed to 0° C., and stirred for 30 min.Water was added and the reaction mixture was extracted with DCM. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was flashchromatographed on a silica gel column with ethyl acetate in hexane from10-30% to afford the desired product (1.07 g). Analytical LCMS:(M+H)⁺=175.2.

Step 3. 1-(1,3-Benzothiazol-6-yl)cyclopropanecarbonitrile

50% aqueous sodium hydroxide (1.51 mL) was added to a mixture of1,3-benzothiazol-6-ylacetonitrile (586 mg, 3.36 mmol),1-bromo-2-chloroethane (335 mg, 4.04 mmol), benzyltriethylammoniumchloride (76.6 mg, 3.36 mmol) at 50° C. The reaction mixture was stirredat 50° C. for 3 h. Water was added and the mixture was extracted withethyl acetate. The combined organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was flash chromatographed on a silica gel column with ethylacetate in hexane from 0-30% to afford the desired product (157 mg,24%). Analytical LCMS: (M+H)⁺=201.2.

Step 4. 1-(1,3-benzothiazol-6-yl)cyclopropanecarboxylic acid

1-(1,3-benzothiazol-6-yl)cyclopropanecarbonitrile (133 mg, 0.664 mmol)was refluxed with 11.3 M of hydrogen chloride in water (5 mL) for 1 h.After cooled to RT, the mixture was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over NaSO₄,filtered, and concentrated under reduced pressure to give the desiredproduct. LCMC: (M+H)⁺=219.9.

Step 5.3-[1-(1,3-benzothiazol-6-yl)cyclopropyl]-6-(4-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine

A mixture of 6-(4-bromophenyl)-3-hydrazino-1,2,4-triazine (20.0 mg,0.0752 mmol) and 1-(1,3-benzothiazol-6-yl)cyclopropanecarboxylic acid(16.5 mg, 0.0752 mmol) in phosphoryl chloride (1 mL) was heated at 130°C. for 8 h. The volatiles were removed under reduced pressure. Theresidue was dissolved in methanol, and purified by RP-HPLC (pH=10) togive the desired product. LCMC: (M+H)⁺=448.9/451.0.

Example 804-{3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-{(1S)-1-[(dimethylamino)carbonyl]propyl}benzamide

Step 1. 1-(1,3-benzothiazol-6-yl)cyclopropanecarbaldehyde

A solution of diisobutylaluminum hydride in toluene (1.00 M, 2.10 mL,0.0021 mol) was slowly added to a solution of1-(1,3-benzothiazol-6-yl)cyclopropanecarbonitrile (0.28 g, 0.0014 mol,prepared in Example 79, Steps 1-3) in toluene (2 mL) at −78° C. Themixture was slowly warmed to RT and stirred overnight. After cooling to−60° C., isopropyl alcohol (0.32 mL) was carefully added. The mixturewas warmed to 0° C., and saturated potassium sodium tartrate (50 mL) wasadded, and stirred at RT for 30 min. The mixture was extracted withethyl acetate (3×40 mL). The organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was flash chromatographed on a silica gel columnwith 40% ethyl acetate in hexanes to afford1-(1,3-benzothiazol-6-yl)cyclopropanecarbaldehyde. Analytical LCMS:(M+H)⁺=204.0.

Step 2. methyl4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoate

A mixture of 1-(1,3-benzothiazol-6-yl)cyclopropanecarbaldehyde (80.0 mg,0.39 mmol) and methyl 4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate (96.5mg, 0.394 mol) in ethanol (2.7 mL) and acetic acid (0.53 mL) was stirredat RT for 3 h. The mixture was concentrated. The residue was dissolvedin DCM (5 mL), followed by addition iodobenzene diacetate (150 mg, 0.47mmol). The mixture was stirred at RT for 6 h, and quenched withsaturated sodium bicarbonate (25 mL). The mixture was extracted withethyl acetate (3×40 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was flash chromatographed on a silica gel columnwith 40% ethyl acetate in DCM to afford the desired product. AnalyticalLCMS: (M+H)⁺=429.0.

Step 3.4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoicacid

A mixture of methyl4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoate(80.0 mg, 0.19 mmol) and lithium hydroxide monohydrate (16.0 mg, 0.37mmol) in methanol (3.0 mL) and water (1.0 mL) was stirred at RT for 4 h.The mixture was adjusted with 1N HCl to pH=5. The volatiles were removedunder reduced pressure, and dried in-vacuo to give a crude product whichwas directly used in the next step without further purification.Analytical LCMS: (M+H)⁺=415.0.

Step 4. (2S)-2-amino-N,N-dimethylbutanamide hydrochloride

Triethylamine (201.9 μL, 1.500 mmol) was added to a solution of(2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (101.6 mg, 0.500 mmol)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (221.1 mg, 0.500 mmol) in DCM (5 mL), followed byaddition of 2.0 M of dimethylamine in tetrahydrofuran (0.500 mL). Themixture was stirred at RT for 4 h. The organic layer was separated. Theaqueous layer was extracted with DCM (3×5 mL). The combined organiclayers were washed with NaHCO₃ (7.5%), and brine, dried over Na₂SO₄,filtered, and concentrated. The residue was treated with HCl in dioxane(4 M, 1.0 mL) at RT for 4 h. The volatiles were evaporated under reducedpressure. The residue was washed with ether and dried in-vacuo to givethe desired product which was directly used in the next step withoutfurther purification. Analytical LCMS: (M+H)⁺=131.1.

Step 5.4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-{(1S)-1-[(dimethylamino)carbonyl]propyl}benzamide

N,N-Diisopropylethylamine (14 μL, 0.080 mmol) was added to a mixture of4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoicacid (11 mg, 0.026 mmol), (2S)-2-amino-N,N-dimethylbutanamidehydrochloride (5.8 mg, 0.034 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(14 mg, 0.032 mmol) in DMF (0.4 mL). The mixture was stirred at RTovernight. The residue was diluted with methanol, and purified byRP-HPLC (pH=10) to afford the desired product. Analytical LCMS:(M+H)⁺=527.0

Example 814-{3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-{(1S)-1-[(dimethylamino)carbonyl]-2-methylpropyl}benzamide

This compound was prepared using procedures analogous to those forExample 80. Analytical LCMS: (M+H)⁺=541.1.

Example 824-{3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-{(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl}benzamide

Step 1.Tert-butyl(2S)-2-[(4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoate

N,N-Diisopropylethylamine (42 μL, 0.24 mmol) was added to a mixture of4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoicacid (33 mg, 0.080 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoatehydrochloride (23 mg, 0.10 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(42 mg, 0.096 mmol) in DMF (1 mL). The mixture was stirred at RTovernight, and quenched with saturated sodium bicarbonate (5 mL). Thereaction mixture was extracted with ethyl acetate (3×5 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue was flashchromatographed on a silica gel column with ethyl acetate in hexanes(40%) to afford the desired product. Analytical LCMS: (M+H)⁺=584.2

Step 2.(2S)-2-[(4-{3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoicacid

A mixture of tert-butyl(2S)-2-[(4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]-triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoate(33.0 mg, 0.056 mmol) in trifluoroacetic acid (1.0 mL) and methylenechloride (1.0 mL) was stirred at RT for 2 h. The volatiles wereevaporated under reduced pressure to afford the desired product whichwas directly used in the next step without further purification.Analytical LCMS: (M+H)⁺=528.0.

Step 3.4-{3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-{(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl}benzamide

N,N-Diisopropylethylamine (14 μL, 0.080 mmol) was added to a mixture of(2S)-2-[(4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoicacid (14 mg, 0.026 mmol), dimethylamine (0.034 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(14 mg, 0.032 mmol) in DMF (0.4 mL). The mixture was stirred at RTovernight. The residue was diluted with methanol, and purified byRP-HPLC (pH=10) to afford the desired product. Analytical LCMS:(M+H)⁺=555.1.

Example 836-(1-{6-[4-(1-Methyl-1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline

A mixture of6-{1-[6-(4-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(25 mg, 0.056 mmol, Example 41),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18mg, 0.084 mmol), tetrakis(triphenylphosphine) palladium(0) (4 mg, 0.003mmol), sodium carbonate (18 mg, 0.17 mmol) in ethanol (400 μL) andtoluene (400 μL) was heated at 150° C. for 2 h, then at 120° C.overnight. The mixture was concentrated. The residue was diluted withmethanol and filtered. The filtrate was purified by RP-HPLC (pH=2) toafford the desired product as a TFA salt. Analytical LCMS: (M+H)⁺=445.1.

Example 84 N-Methyl-5-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridine-2-carboxamide

This compound was prepared using procedures analogous to those forExample 83. Analytical LCMS: (M+H)⁺=499.1.

Example 85 N,N-Dimethyl-5-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenylpyridine-2-carboxamide

This compound was prepared using procedures analogous to those forExample 83. Analytical LCMS: (M+H)⁺=513.1.

Example 866-(1-{6-[4-(1H-pyrazol-1-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline

A mixture of6-{1-[6-(4-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(20 mg, 0.04 mmol, Example 41), 1H-pyrazole (4.6 mg, 0.068 mmol),potassium phosphate (20 mg, 0.095 mmol),N,N′-dimethylcyclohexane-1,2-diamine (1.4 μL), and copper(I) iodide (1.7mg) in 1,4-dioxane (500 μL) was heated at 150° C. for 2 h. Aftercooling, the mixture was diluted with methanol and filtered. Thefiltrate was purified by RP-HPLC (pH=10) to afford the desired product.Analytical LCMS: (M+H)⁺=431.1.

Example 87 N-(Cyclopropylmethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

Step 1. Methyl 4-(oxoacetyl)benzoate

To a solution of 4-acetylbenzoic acid methyl ester (25 g, 0.14 mol) indimethyl sulfoxide (300 mL) was added slowly a solution of hydrogenbromide in water (48%, 48 mL) at RT with stirring. The mixture wasstirred at 60° C. overnight. After cooling it was poured into ice-water.The formed precipitate was collected by filtration and dried in-vacuo toafford the desired product (15.6 g, 79%).

Step 2. Methyl 4-(diethoxyacetyl)benzoate

A mixture of methyl 4-(oxoacetyl)benzoate (13.5 g, 0.0702 mol), ethylorthoformate (29 mL, 0.18 mol), p-toluenesulfonic acid monohydrate (0.7g) in toluene (150 mL) was heated under reflux for 2 h. After cooling,the solvent was removed under reduced pressure. The crude material wasflash chromatographed on a silica gel column to afford the desiredproduct (15.4 g, 82%). Analytical LCMS: (M+Na)⁺=289.0.

Step 3. Methyl 4-(3-oxo-2,3-dihydro-1,2,4-triazin-6-yl)benzoate

A mixture of methyl 4-(diethoxyacetyl)benzoate (15.4 g, 0.0578 mol),semicarbazide hydrochloride (7.1 g, 0.064 mol),N,N-diisopropylethylamine (12 mL, 0.069 mol) in 1,2-dichloroethane (150mL), and methanol (2 mL) was heated at 95° C. for 4 h. To the mixturewas added an additional 0.1 equivalents of semicarbazide hydrochloride.The mixture was stirred at 95° C. for 1 h. After cooling, the mixturewas diluted with methylene chloride and washed with water and brine,dried over Na₂SO₄, filtered, and concentrated. The residue was refluxedwith acetic acid (100 mL) and water (1.0 mL) overnight. The mixture wasconcentrated to yield quantitative crude material which was directlyused in the next step without further purification.

Step 4. Methyl 4-(3-chloro-1,2,4-triazin-6-yl)benzoate

A mixture of methyl 4-(3-oxo-2,3-dihydro-1,2,4-triazin-6-yl)benzoate(13.4 g, 0.0580 mol), phosphoryl chloride (30 mL, 0.3 mol) in chloroform(50 mL) was heated at reflux (oil-bath temperature about 100° C.) for 2h. After cooling, the mixture was concentrated to remove excessphosphoryl chloride. The residue was dissolved in DCM. The solution waspoured into ice-water, and carefully neutralized with K₂CO₃. The organiclayer was separated. The aqueous solution was extracted with methylenechloride. The combined extracts were dried over Na₂SO₃. After filtrationthe filtrate was concentrated and further purified by flash column toafford the desired product (2.5 g, 17%). Analytical LCMS: (M+H)⁺=249.9.¹H NMR (300 MHz, CDCl₃): δ(ppm) 3.98 (s, 3H), 8.18 (d, 2H), 8.24 (d,2H), 8.96 (s, 1H).

Step 5. Methyl 4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate

To a solution of methyl 4-(3-chloro-1,2,4-triazin-6-yl)benzoate (1.1 g,0.0044 mol) in tetrahydrofuran (30 mL) was added hydrazine hydrate (1.1mL, 0.022 mol) at RT with stirring. The mixture was stirred at RT for 1h, and concentrated under reduced pressure to give the desired product(quantitatively). Analytical LCMS: (M+H)⁺=245.9.

Step 6. Methyl4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate

A mixture of methyl 4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate (115 mg,0.000469 mol) and 1-quinolin-6-ylcyclopropanecarbaldehyde (92 mg,0.00047 mol) in ethanol (2 mL) and acetic acid (0.5 mL) was stirred atRT for 6 h. The volatiles were removed under reduced pressure. Theresidue was dried under high vacuum, and then dissolved in methylenechloride (6 mL). To the solution was added iodobenzene diacetate (180mg, 0.00056 mol). The reaction mixture was stirred at RT overnight. Thesolvent was evaporated and the residue was flash chromatographed on asilica gel column to afford the desired product (120 mg, 60%).Analytical LCMS: (M+H)⁺=423.3.

Step 7.N-(Cyclopropylmethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

To a solution of methyl4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate(15 mg, 0.036 mmol) in toluene (0.2 mL) was added 2.0 M oftrimethylaluminum in toluene (27 μL) at RT followed by addition ofcyclopropylmethylamine (5.0 mg, 0.071 mmol). The mixture was stirred at70° C. overnight. After cooling the mixture was diluted with methanol,and filtered. The filtrate was purified by RP-HPLC (pH=10) to afford thedesired product. Analytical LCMS: (M+H)⁺=462.4.

Example 88 N-Ethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 87. Analytical LCMS: (M+H)⁺=436.0. ¹H-NMR (400 MHz, DMSO-d₆):1.12 (t, 3H), 1.72 (m, 2H), 1.84 (m, 2H), 3.28 (q, 2H), 7.66 (m, 1H),7.82 (d, 1H), 7.96 (m, 2H), 8.02 (m, 3H), 8.06 (d, 1H), 8.58 (m, 1H),8.62 (m, 1H), 9.00 (m, 1H), 9.38 (s, 1H).

Example 89 N,N-Dimethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 87. Analytical LCMS: (M+H)⁺=436.0.

Example 90 N-Cyclopropyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 87. Analytical LCMS: (M+H)⁺=448.4.

Example 91 N-(Pyridin-2-ylmethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

Step 1.4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoicacid

Methyl 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate (300 mg, 0.7 mmol)was dissolved in 6 ml of THF-MeOH—H₂O (3:1:1). To the solution was addeda solution of 2.0 M of lithium hydroxide in water (710 μL) with stirringunder N₂ atmosphere. The mixture was stirred at RT for 1 h, and thenneutralized with aqueous HCl solution (1.0 M, 1.420 mL). The whiteprecipitate formed was collected by filtration, and dried in-vacuo togive the desired product (210 mg, 72%). Analytical LCMS: m/z 409.0(M+H).

Step 2.N-(pyridin-2-ylmethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

A mixture of4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoicacid (10 mg, 0.00002 mol), 2-pyridinemethanamine (2.9 mg, 0.000027 mol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(12 mg, 0.000027 mol), N,N-diisopropylethylamine (11 μL, 0.000061 mol)in DMF (0.4 mL) was stirred at RT for 2 h. The mixture was diluted withmethanol and purified by RP-HPLC (pH=10) to afford the desired product.Analytical LCMS: (M+H)⁺=499.1.

Example 92 Ethyl 4-{4-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoyl}piperazine-1-carboxylate

This compound was prepared using procedures analogous to those forExample 91. Analytical LCMS: (M+H)⁺=549.2.

Example 936-(1-{6-[4-(Pyrrolidin-1-ylcarbonyl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline

This compound was prepared using procedures analogous to those forExample 91. Analytical LCMS: (M+H)⁺=462.1.

Example 946-[1-(6-{4-[(3,3-Difluoropyrrolidin-1-yl)carbonyl]phenyl}[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]quinoline

This compound was prepared using procedures analogous to those forExample 91. Analytical LCMS: (M+H)⁺=498.1.

Example 956-{1-[6-(4-{[3-(3-Fluorophenyl)pyrrolidin-1-yl]carbonyl}phenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline

This compound was prepared using procedures analogous to those forExample 91. Analytical LCMS: (M+H)⁺=556.1.

Example 96 6-{1-[6-(4-{[(3S)-3-Fluoropyrrolidin-1-yl]carbonyl}phenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline

This compound was prepared using procedures analogous to those forExample 91. Analytical LCMS: (M+H)⁺=480.1. ¹H-NMR (400 MHz, CD₃OD): 9.27(s, 1H), 8.79 (dd, J=4.4, 1.6 Hz, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.04 (m,3H), 7.98 (d, J=8.8 Hz, 1H), 7.85 (dd, J=9.0, 2.2 Hz, 1H), 7.67 (dd,J=8.4, 5.4 Hz, 2H), 7.57 (dd, J=8.4, 4.4 Hz, 1H), 5.30 (m, 1H),3.88-3.53 (m, 4H), 2.36-2.14 (m, 2H), 1.91 (m, 2H), 1.77 (m, 2H).

Example 97 4-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]benzamide

This compound was prepared using procedures analogous to those forExample 91. Analytical LCMS: (M+H)⁺=492.1.

Example 98N-(1-Pyridin-2-ylcyclopropyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

Step 1. 1-pyridin-2-ylcyclopropanamine

To a solution of 2-pyridinecarbonitrile (1.00 g, 9.60 mmol) in ether (30mL) were added successively at RT titanium tetraisopropoxide (3.1 mL,10.0 mmol) and 1.0 M of ethylmagnesium bromide in tetrahydrofuran (19mL). After the mixture was stirred for 30 min, water (5.0 mL) was added.The mixture was extracted with diethyl ether. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated to afford the crude product which was directly used in thenext step without further purification.

Step 2.N-(1-pyridin-2-ylcyclopropyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 91. Analytical LCMS: (M+H)⁺=525.1.

Example 99N-(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

Step 1. tert-butyl(2S)-3,3-dimethyl-2-({4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoyl}amino)butanoate

A mixture of4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoicacid (40 mg, 0.10 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoatehydrochloride (26 mg, 0.12 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(45.5 mg, 0.103 mmol), and N,N-diisopropylethylamine (60 μL, 0.34 mmol)in methylene chloride (1.5 mL) was stirred at RT overnight. The mixturewas diluted with DCM, and washed with saturated NaHCO₃ solution, waterand brine, dried over Na₂SO₄, filtered, and concentrated to yielddesired product which was directly used in the next step without furtherpurification.

Step 2.(2S)-3,3-dimethyl-2-({4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoyl}amino)butanoicacid

Tert-butyl-(2S)-3,3-dimethyl-2-({4-[3-(1-quinolin-6-ylcyclopropyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoyl}amino)butanoatewas dissolved in methylene chloride (0.7 ml). To the solution was addedTFA (0.7 ml). The mixture was stirred for 1.5 h. The volatiles wereremoved under reduced pressure to yield the desired product. AnalyticalLCMS: (M+H)⁺=522.2.

Step 3.N-(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

A mixture of(2S)-3,3-dimethyl-2-(4-[3-(1-quinolin-6-ylcyclopropyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoylamino)butanoicacid (12 mg, 0.023 mmol), 2.00 M of methylamine in tetrahydrofuran (23μL), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (15 mg, 0.034 mmol) and N,N-diisopropylethylamine(16 μL, 0.092 mmol) in methylene chloride (0.5 mL) was stirred at RT for3 h. The solvent was evaporated. The residue was dissolved in methanol,and purified by RP-HPLC (pH=10) to afford the desired product.Analytical LCMS: (M+H)⁺=535.2.

Example 100N-{(1S)-1-[(Dimethylamino)carbonyl]-2,2-dimethylpropyl}-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 99. Analytical LCMS: (M+H)⁺=549.2.

Example 101N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 99. Analytical LCMS: (M+H)⁺=561.2.

Example 102N-[(1S)-2-Amino-1-methyl-2-oxoethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

Step 1. benzyl [(1S)-2-amino-1-methyl-2-oxoethyl]carbamate

A mixture of (2S)-2-[(benzyloxy)carbonyl]aminopropanoic acid (0.5 g,0.002 mol), ammonium carbonate (0.43 g, 0.0045 mol),benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(1.2 g, 0.0027 mol), N,N-diisopropylethylamine (980 μL, 0.0056 mol) inmethylene chloride (3 mL) was stirred at RT overnight. The mixture wasquenched with saturated NaHCO₃ solution, and extracted with DCM. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue was flashchromatographed on a silica gel column to afford the desired product(0.54 g). Analytical LCMS: (M+H)⁺=223.1.

Step 2. (2S)-2-aminopropanamide

A mixture of benzyl [(1S)-2-amino-1-methyl-2-oxoethyl]carbamate inmethanol (10 ml) with 10% Pd on charcoal catalyst (10 mg) was stirredunder H₂ atmosphere (balloon) for 1 h. The mixture was filtered. Thefiltrate was concentrated to yield the desired product.

Step 3.N-[(1S)-2-amino-1-methyl-2-oxoethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

A mixture of4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoicacid (10 mg, 0.02 mmol), (2S)-2-aminopropanamide (3.2 mg, 0.037 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(13 mg, 0.029 mmol), and N,N-diisopropylethylamine (13 μL, 0.073 mmol)in methylene chloride (0.5 mL) was stirred at RT overnight. The solventwas evaporated. The residue was dissolved in methanol, and purified byRP-HPLC (pH=10) to afford the desired product. Analytical LCMS:(M+H)⁺=479.0.

Example 103N-[(1S)-1-(Aminocarbonyl)-2-methylpropyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 102. Analytical LCMS: (M+H)⁺=507.1.

Example 104 N-Ethyl-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

Step 1. methyl 4-acetyl-2-fluorobenzoate

A mixture of methyl 4-bromo-2-fluorobenzoate (7.0 g, 0.030 mol),1-(ethenyloxy)butane (13 mL, 0.099 mol), palladium acetate (200 mg,0.0009 mol), 1,3-bis(diphenylphosphino)propane (700 mg, 0.002 mol), andpotassium carbonate (4.29 g, 0.0310 mol) in DMF (50 mL) and water (3 mL)was heated at 80° C. with stirring for 24 h. After cooling to RT, to thesolution was added 1N HCl solution (31 ml). The mixture was stirred atRT for 1 h, and then extracted with ethyl ether. The combined extractswere washed with brine; dried over Na₂SO₄, filtered concentrated. Theresidue was flash chromatographed on a silica gel column to give thedesired product (1.64 g).

Step 2. methyl 2-fluoro-4-(oxoacetyl)benzoate

A mixture of methyl 4-acetyl-2-fluorobenzoate (1.6 g, 0.0082 mol), 48%of hydrogen bromide aqueous solution (2.8 mL) in dimethyl sulfoxide (20mL) was stirred at 60° C. overnight. After cooling, the mixture waspoured into ice-water. The product was extracted with ethyl ether. Thecombined extracts were washed with brine; dried over Na₂SO₄, filteredconcentrated to yield 1.60 g of the product which was directly used inthe next step without further purification.

Step 3. methyl 4-(diethoxyacetyl)-2-fluorobenzoate

A mixture of methyl 2-fluoro-4-(oxoacetyl)benzoate (1.60 g), ethylorthoformate (5.2 mL), p-toluenesulfonic acid monohydrate (70 mg) intoluene (20 mL) was heated under reflux for 3 h. After cooling, themixture was concentrated. The residue was flash chromatographed on asilica gel column to give the desired product (0.63 g).

Step 4. methyl4-(5-ethoxy-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-2-fluorobenzoate

A mixture of methyl 4-(diethoxyacetyl)-2-fluorobenzoate (0.63 g, 0.0022mol), thiosemicarbazide (0.24 g, 0.0026 mol), and p-toluenesulfonic acidmonohydrate (20 mg) in ethanol (6 mL) was heated at 90° C. for 1.5 h.After cooling to RT, to the mixture was added methyl iodide (0.7 mL,0.01 mol). The mixture was stirred at RT for 1 h. The mixture wasconcentrated. The residue was dissolved in acetic acid (4 mL), andheated at 60° C. for 2 h. After cooling, the reaction mixture wasconcentrated. The residue was treated with methanol. The formedprecipitate was collected by filtration, and dried in-vacuo to affordthe desired product (180 mg). Analytical LCMS: (M+H)⁺=280.0.

Step 5. methyl2-fluoro-4-[3-(methylsulfinyl)-1,2,4-triazin-6-yl]benzoate

To a cooled (0° C.) solution of methyl2-fluoro-4-[3-(methylthio)-1,2,4-triazin-6-yl]benzoate (0.180 g,0.000644 mol) in methylene chloride (10 mL) was added m-chloroperbenzoicacid (0.32 g, 0.0014 mol) in DCM (3 ml) with stirring. The mixture wasstirred at 0° C. for 1.5 h, and diluted with DCM. The resulting solutionwas quenched with saturated Na₂S₂O₃ solution. After separation theorganic layer was washed with saturated NaHCO₃ solution, brine; anddried over Na₂SO₄. After filtration the filtrate was concentrated toyield nearly quantitative product which was directly used in the nextstep without further purification. Analytical LCMS: (M+H)⁺=296.0.

Step 6. methyl 2-fluoro-4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate

To a suspension of methyl2-fluoro-4-[3-(methylsulfinyl)-1,2,4-triazin-6-yl]benzoate (0.19 g,0.00064 mol) in tetrahydrofuran (20 mL) was added hydrazine hydrate (63μL, 0.0013 mol) slowly. The mixture was stirred at RT for 1.5 h. Themixture was concentrated under reduced pressure to yield the desiredproduct. Analytical LCMS: (M+H)⁺=264.1.

Step 7. methyl2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate

A mixture of methyl 2-fluoro-4-(3-hydrazino-1,2,4-triazin-6-yl)benzoate(0.17 g, 0.64 mmol) and 1-quinolin-6-ylcyclopropanecarbaldehyde (0.13 g,0.64 mmol) in ethanol (10 mL) and acetic acid (1 mL) was stirred at RTfor 2 h. The mixture was concentrated. The residue was dissolved inmethylene chloride (5 mL). To the solution was added iodobenzenediacetate (230 mg, 0.71 mmol) with stirring. The mixture was stirred atRT for 2 h then concentrated. The residue was flash chromatographed on asilica gel column to give the desired product (150 mg). Analytical LCMS:(M+H)⁺=441.0.

Step 8.2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoicacid

Methyl 2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate (0.15 g, 0.34 mmol)was dissolved in a solution of tetrahydrofuran (3 mL), methanol (1 mL)and water (1 mL) under N₂ atmosphere. To the solution was added lithiumhydroxide aqueous solution (2.0 M, 0.30 mL) with stirring. The mixturewas stirred at RT for 1 h, and acidified with 1.0 M of hydrogen chloridein water (0.68 mL). The organic solvents were removed. The formedprecipitate was collected by filtration, and dried in-vacuo to affordthe desired product (120 mg). Analytical LCMS: (M+H)⁺=427.0.

Step 9.N-ethyl-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

A mixture of2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoicacid (10 mg, 0.02 mmol), 2.0 M of ethylamine in tetrahydrofuran (23 μL),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(12 mg, 0.028 mmol), and N,N-diisopropylethylamine (10.0 μL, 0.059 mmol)in methylene chloride (0.5 mL) was stirred at RT for 2 h. The solventwas evaporated. The residue was dissolved in methanol, and purified byRP-HPLC (pH=10) to afford the desired product. Analytical LCMS:(M+H)⁺=454.0. ¹H-NMR (400 MHz, CD₃OD): 1.12 (t, 3H), 1.84 (m, 2H), 2.02(m, 2H), 3.42 (q, 2H), 7.80 (m, 2H), 7.90 (d, 2H), 7.98 (m, 1H), 8.18(m, 2H), 8.32 (d, 1H), 9.00 (d, 1H), 9.10 (d, 1H), 9.32 (s, 1H).

Example 105 2-Fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 104. Analytical LCMS: (M+H)⁺=440.0. ¹H-NMR (400 MHz, CD₃OD):1.87 (m, 2H), 2.03 (m, 2H), 2.94 (s, 3H), 7.77 (dd, J=11.5, 1.3 Hz, 1H),7.85 (dd, J=7.9; 7.3 Hz, 1H), 7.91 (dd, J=8.1, 1.5 Hz, 1H), 8.02 (dd,J=8.3 Hz, 5.4; 1H), 8.17 (m, 1H), 8.17 (m, 1H), 8.33 (s, 1H), 9.06 (dd,J=8.1, 1.2 Hz, 1H), 9.13 (dd, J=5.3, 1.4 Hz, 1H), 9.31 (s, 1H).

Example 1062-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 104. Analytical LCMS: (M+H)⁺=524.1.

Example 1072-Fluoro-N-(2-methoxy-1,1-dimethylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 104. Analytical LCMS: (M+H)⁺=512.1.

Example 108 N-Cyclopropyl-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 104. Analytical LCMS: (M+H)⁺=466.0.

Example 109 2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 104. Analytical LCMS: (M+H)⁺=426.0. ¹H-NMR (400 MHz, CD₃OD):1.86 (m, 2H), 2.03 (m, 2H), 7.77 (d, 1H), 7.90 (m, 2H), 7.98 (m, 1H),8.18 (m, 2H), 8.32 (d, 1H), 9.00 (d, 1H), 9.10 (d, 1H), 9.32 (s, 1H).

Example 110 2-Fluoro-N,N-dimethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

This compound was prepared using procedures analogous to those forExample 104. Analytical LCMS: (M+H)⁺=454.1.

Example 1116-(1-{6-[3-Fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline

This compound was prepared using procedures analogous to those forExample 104. Analytical LCMS: (M+H)⁺=480.0.

Example 112N-Methyl-N-2-[methyl(pyridin-2-yl)amino]ethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

Step 1. tert-butyl 2-[methyl(pyridin-2-yl)amino]ethylcarbamate

A solution of tert-butyl [2-(methylamino)ethyl]carbamate hydrochloride(0.30 g, 0.0014 mol), 2-chloropyridine (160 mg, 0.0014 mol), andtriethylamine (300 μL, 0.0021 mol) in acetonitrile (5 mL) was heated at90° C. overnight. The mixture was diluted with methanol, and purified byRP-HPLC (pH=10) to afford the desired product. Analytical LCMS:(M+H)⁺=252.1

Step 2. N-methyl-N-pyridin-2-ylethane-1,2-diamine trifluoroacetate

tert-Butyl 2-[methyl(pyridin-2-yl)amino]ethylcarbamate was stirred withDCM (0.5 ml) and TFA (0.5 ml) for 30 min. The volatiles were removedunder reduced pressure to yield the product.

Step 3.N-methyl-N-2-[methyl(pyridin-2-yl)amino]ethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

A mixture of4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoicacid (10 mg, 0.02 mmol), N-methyl-N-pyridin-2-ylethane-1,2-diaminetrifluoroacetate (6.1 mg, 0.037 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(13 mg, 0.029 mmol), and N,N-diisopropylethylamine (13 μL, 0.073 mmol)in methylene chloride (0.5 mL) was stirred at RT for 2 h. The solventwas evaporated. The residue was dissolved in methanol, and purified byRP-HPLC (pH=10) to afford the desired product. Analytical LCMS:(M+H)⁺=556.2.

Example 113N-[(1R)-1-(4-Methyl-1,3-thiazol-2-yl)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

Step 1. tert-butyl [(1R)-2-amino-1-methyl-2-thioxoethyl]carbamate

2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (1.6g, 0.0038 mol) was added to a solution of tert-butyl[(1R)-2-amino-1-methyl-2-oxoethyl]carbamate (1.45 g, 0.00770 mol) in1,2-dimethoxyethane (40 mL). The resulting suspension was stirred at RTfor 5 h. After removal of solvent the residue was taken up into ethylacetate. It was washed with 0.1 N NaOH solution, water, brine; driedover Na₂SO₄. After filtration the filtrate was concentrated to yield1.58 g of the product. (yield: ˜100%).

Step 2. tert-butyl [(1R)-1-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate

A mixture of tert-butyl [(1R)-2-amino-1-methyl-2-thioxoethyl]carbamate(100 mg, 0.49 mmol) with 3 equivalents of chloroacetone (0.135 g) inethanol (1 mL) was heated at 80° C. for 2 h. After cooling, the solutionwas concentrated. The residue was dissolved in DCM (1 ml). To thesolution was added TFA (1 mL). The mixture was stirred at RT for 30 min.The volatiles were removed under reduced pressure to yield desiredproduct.

Step 3.N-[(1R)-1-(4-methyl-1,3-thiazol-2-yl)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide

A mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoic acid (10 mg, 0.02mmol), (1R)-1-(4-methyl-1,3-thiazol-2-yl)ethanaminebis(trifluoroacetate) (14 mg, 0.037 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(14 mg, 0.032m mol), and N,N-diisopropylethylamine (21 μL, 0.12 mmol) inmethylene chloride (0.5 mL) was stirred at RT for 2 h. The solvent wasevaporated. The residue was dissolved in methanol, and purified byRP-HPLC (pH=10) to afford the desired product. Analytical LCMS:(M+H)⁺=533.1.

Example A In Vitro c-Met Kinase Enzyme Assays

Compounds were screened in vitro for their ability to inhibit c-Metkinase activity. The IC₅₀ values of compounds for the inhibition ofc-Met kinase were determined as described in the literature with somemodifications (Wang, X. et al, Mol. Cancer. Ther. 2003, 2(11):1085-1092;Calic, M. et al., Croatica Chemical ACTA. 2005, 78(3):367-374). Briefly,histidine-tagged c-Met catalytic domain fusion protein (Invitrogen, #PV3143) was used for the assay. IC₅₀ measurements were based on thedegree of phosphorylation of poly Glu-Tyr (Sigma-Aldrich, # P0275) thatwas coated (0.01 mg/per well) on 96-well microplates (R&D systems, #DY990). The reaction was carried out in a 50 μL solution containing 50mM HEPES (pH 7.5), 10 mM MnCl₂, 10 mM MgCl₂, 0.5 mM DTT, 100 μM Na₃VO₄,5 μM ATP (Cell Signaling Technology, # 9804) and serial dilutions ofindividual compounds. The reaction lasted for 25 minutes at 30° C. Afterthe reaction was completed, the contents of the plates was discarded.Plates were then washed with TBS-T (250 μL/well, 5×) and then blockedwith TBS-T containing 1% BSA for 2 hours. The contents of the plates wasdiscarded, and 100 μL (per well) of peroxidase-labeledanti-phospho-tyrosine antibody (Sigma, # A5964) diluted (1:60,000) in 1%BSA containing TBS-T were then added and incubated for 1 hour. Plateswere washed with TBS-T (250 μL/well, 5×) and followed by the colorreaction using 100 μL (1:1 mixture) of H₂O₂ and tetramethylbenzidine(R&D Systems, # DY999). The reaction was stopped in minutes with 100 μLof 2 NH₂SO₄. The optical density was measured immediately using amicroplate reader at 450 nm with wavelength correction at 540 nm. IC₅₀values were calculated with the GraphPad Prism software. The linearrange (i.e., the time period over which the rate remained equivalent tothe initial rate) was determined for the kinase and IC₅₀ determinationswere performed within this range. Compounds having an IC₅₀ of 20 μM orless were considered active. The IC₅₀ value for the compound of Example26 according to this assay was found to be 12.9 nM. The other Examplecompounds were also found to be active.

Wang, X., et al. Potent and selective inhibitors of the Met [hepatocytegrowth factor/scatter factor (HGF/SF) receptor] tyrosine kinase blockHGF/SF-induced tumor cell growth and invasion. Mol. Cancer. Ther. 2003,2(11): 1085-1092.

Calic, M., et al. Flavonoids as inhibitors of Lck and Fyn kinases.Croatica Chemica ACTA. 2005, 78(3):367-374.

Example B Cell Proliferation/Survival Assays

Cell lines representing various human cancers (SNU-1 and SUN-5 gastric,A549 and NCI-H441 lung, U-87 glioblastoma, HT-29 colon, 786-O kidney,PC-3 pancreatic) were obtained from American Type Culture Collection androutinely maintained in culture media and conditions recommended byATCC. Optimal cell density used in proliferation/survival assay waspredetermined for individual cell lines. Compounds were screened fortheir ability to inhibit cell proliferation/survival, and IC₅₀ valueswere determined. Below are the sample protocols for SNU-5 and SNU-1 cellproliferation/survival assays. SNU-5 and SNU-1 cells were seeded into 96well cell culture plates at 4000 cells/well and 2000 cells/wellrespectively in appropriate media containing 2% FBS and supplementedwith serial dilutions of individual compounds in a final volume of 100μL/well. After 72 hour incubation, 24 μL of CellTiter 96® AQueous OneSolution reagent (Promega, # G3581) were added to each well (finalconcentration=333 μg/mL), and the plates were incubated for 2 more hoursin a 37° C. incubator. The optical density was measured in the linearrange using a microplate reader at 490 nm with wavelength correction at650 nm. IC₅₀ values were calculated with the GraphPad Prism software.For proliferation assays using A549, NCI-H441, U-87, HT-29, 786-0 andPC-3 cells, the cells were first starved for 48 hours in low serumcondition (0.1-0.5% FBS in appropriate culture media), then treated withdifferent concentrations of compounds for 2 hours. After the cells weretreated with HGF (50 ng/mL) (R&D, # 294-HGN) for 24 hours, CellTiter 96®AQueous One Solution reagent was added and plates were incubated for 2hours. The results were recorded with a plate reader. Compounds havingan IC₅₀ of 20 μM or less were considered active.

Example C Cell-Based c-Met Phosphorylation Assays

The inhibitory effect of compounds on c-Met phosphorylation in relevantcell lines (SNU-5 gastric, A549 and NCI-H441 lung, U-87 glioblastoma,HT-29 colon, 786-O kidney and PC-3 pancreatic cancer cell lines andHUVEC cell line) was assessed using immunoblotting analysis andELISA-based c-Met phosphorylation assays. Cells were grown inappropriate culture media and treated with various concentrations ofindividual compounds. For SNU-5, HT-29, 786-0 cells, cells were grown inappropriated media supplemented with 0.2% or 2% FBS and treated withcompounds for 3-4 hours. Whole cell protein extracts were prepared usingreagents and a protocol (# FNN0011) obtained from BiosourceInternational with slight modifications. Briefly, protein extracts weremade by incubation in lysis buffer with protease and phosphataseinhibitors [50 mM HEPES (pH 7.5), 100 mM NaCl, 1.5 mM MgCl₂, 10%Glycerol, 1% Triton X-100, 1 mM sodium orthovanadate, 1 mM sodiumfluoride, aprotinin (2 μg/mL), leupeptin (2 μg/mL), pepstatin A (2μg/mL), and phenylmethylsulfonyl fluoride (1 mM)] at 4° C. Proteinextracts were cleared of cellular debris by centrifugation at 14,000×gfor 20 minutes. For A549, H441, U-87 and PC-3 cells, cells were serum(0.2% FBS) starved for at least 24 hours, then pretreated with variousconcentrations of compounds for 1 hour. Whole cell extracts wereprepared after the cells were treated with HGF (50 ng/mL) for 10minutes.

Immunoblotting Analysis

Relevant antibodies were obtained from commercial sources: rabbitpolyclonal antibodies included anti-human c-Met (Santa CruzBiotechnology, # sc-161) and anti-phosphorylated-c-Met (BiosourceInternational, pY1230/4/5 and pY1003). For immunoblotting, 10-20 μg ofprotein extracts from individual treatment conditions were resolved byelectrophoresis on 10% SDS-PAGE gel, and electrotransferred to anitrocellulose (or PVDF) membrane. The membrane was blocked in PBScontaining 3% milk and 0.1% Tween-20 for 1 hour, and then incubated withprimary anti-c-Met antibodies in blocking solution for 1 hour. After 3washes, the membrane was incubated with appropriatehorseradish-conjugated secondary antibodies for 1 hour. After finalwash, the blot was incubated with chemiluminescence detection reagentfor 5 minutes and exposed to X-ray film. The images were scanned,quantified and corrected with total c-Met, and IC₅₀ values werecalculated. Compounds having an IC₅₀ of 20 μM or less were consideredactive.

ELISA

Cell protein extracts were analyzed using a human phospho-c-Met ELISAkit according to the manufacturer's instructions (R&D Systems,#DYC2480). Optimal amounts of protein extracts were predetermined forindividual cell lines. Briefly, for the assay, appropriate amounts ofprotein extracts were captured with a capture anti-human c-Met antibodyfor 2 hours in a 96 well microplate. After washes, a detection antibody(HRP-conjugated anti-phospho-tyrosine antibody) was added and incubatedfor 2 hours. After additional washes, 100 μL of substrate solution (1:1mixture of H₂O₂ and tetramethylbenzidine) were added into each well andthe reaction was stopped with 2 N H₂SO₄ within an appropriate amount oftime during color development. The optical density was measured in thelinear range using a microplate reader at 450 nm with wavelengthcorrection at 540 nm. IC₅₀ values were calculated with the GraphPadPrism software. Compounds having an IC₅₀ of 20 μM or less wereconsidered active.

Example D Assays to Assess Inhibition of c-Met Phosphorylation In VivoMice

Female Balb/c nu/nu mice, 6-8 weeks old, were acquired from CharlesRiver Laboratories (Wilmington, Mass.) and were maintained according toNIH standards. Animal studies were performed under Animal WelfareRegulation Guidelines in a facility accredited by the Association forthe Assessment and Accreditation of Laboratory Animal Care (AAALAC).

Generation of Tumors

S114 cells, murine NIH 3T3 cells engineered to coexpress the human c-Metreceptor and human hepatocyte growth factor (HGF) which were licensedfrom the NIH, were grown in culture in DMEM supplemented with 10% FBS.Cells were kept at 37° C. in a humidified incubator supplied with 5%CO₂—Prior to inoculation, logarithmically growing cells were washed,counted and resuspended in PBS. Injections of 5×10⁶ cells in 0.1 mL weremade into the right flank of Balb/c nu/nu mice. After 6-9 days, whentumor volumes reached an average of 125-400 mm³, depending on theexperiment, mice were randomized for testing in vivo compound potency.

Treatment and Sample Harvest

Tumor bearing mice were administered a single dose of 5-50 mg/kgcompound orally in 5% DMAC in 0.5% methylcellulose. At various timesbetween 1-8 hours post dose administration, mice were humanelyeuthanized using 100% CO₂ and tumors were excised, placed directly intolysis buffer with protease and phosphatase inhibitors [50 mM HEPES (pH7.5), 100 mM NaCl, 1.5 mM MgCl₂, 10% Glycerol, 1% Triton X-100, 1 mMsodium orthovanadate, 1 mM sodium fluoride, aprotinin (2 μg/mL),leupeptin (2 μg/mL), pepstatin A (2 μg/mL), and phenylmethylsulfonylfluoride (1 mM)] at 4° C. and processed for determination of c-Metphosphorylation by ELISA (described in Example C above). Terminal bloodswere harvested for the determination of circulating compound levels inplasma. Data were graphed and analyzed using GraphPad Prism 3.0.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein: Cy¹ is aryl,heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substitutedby 1, 2, 3, 4, or 5 -W—X—Y—Z; Cy² is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5-W′—X′—Y′—Z′; A is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(A), SR^(A), C(O)R^(B), C(O)NR^(C)R^(D),C(O)OR^(A), OC(O)R^(B), OC(O)NR^(C)R^(D), NR^(C)R^(D), NR^(C)C(O)R^(B),NR^(C)C(O)NR^(C)R^(D), NR^(C)C(O)OR^(A), S(O)R^(B), S(O)NR^(C)R^(D),S(O)₂R^(B), NR^(C)S(O)₂R^(B), or S(O)₂NR^(C)R^(D); R¹ and R² togetherwith the carbon atom to which they are attached form a 3- to 7-memberedcycloalkyl group or 3- to 7-membered heterocycloalkyl group, eachoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from Q, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(g))NR^(c)R^(d)NR^(c)C(═NR^(g))NR^(c)R^(d), P(R^(f))₂, P(OR^(e))₂,P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl is optionally substituted with 1,2, or 3 substituents selected from Q, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(g))NR^(c)R^(d). NR^(c)C(NR^(g))NR^(c)R^(d), P(R^(f))₂,P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); Qis aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4, or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halosulfanyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)NR^(c1)R^(d1). NR^(c1)C(O)OR^(a1),C(NR^(g1))NR^(c1)R^(d1), NR^(c1)C(═NR^(g1))NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); W and W′ are independently absent or independentlyselected from C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, O, S,NR^(h), CO, COO, CONR^(h), SO, SO₂, SONR^(h) and NR^(h)CONR^(i), whereineach of the C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene isoptionally substituted by 1, 2 or 3 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,amino, C₁₋₆ alkylamino, and C₂₋₈ dialkylamino; X and X′ areindependently absent or independently selected from C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, arylene, cycloalkylene, heteroarylene, andheterocycloalkylene, wherein each of the C₁₋₆ alkylene, C₂₋₆ alkenylene,C₂₋₆ alkynylene, arylene, cycloalkylene, heteroarylene, andheterocycloalkylene is optionally substituted by 1, 2 or 3 substituentsindependently selected from halo, CN, NO₂, OH, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₂₋₈ alkoxyalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₈alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR^(j), C(O)NR^(h)R^(i),amino, C₁₋₆ alkylamino, and C₂₋₈ dialkylamino; Y and Y′ areindependently absent or independently selected from C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, O, S, NR^(h), CO, COO, CONR^(h), SO, SO₂,SONR^(h), and NR^(h)CONR^(i), wherein each of the C₁₋₆ alkylene, C₂₋₆alkenylene, and C₂₋₆ alkynylene is optionally substituted by 1, 2 or 3substituents independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, andC₂₋₈ dialkylamino; Z and Z′ are independently selected from H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)_(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halosulfanyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein twoadjacent —W—X—Y—Z, together with the atoms to which they are attached,optionally form a fused 4-, 5-, 6-, or 7-membered cycloalkyl ring or afused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring, each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)O^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl; wherein two adjacent —W′—X′—Y′—Z′,together with the atoms to which they are attached, optionally form afused 4-, 5-, 6-, or 7-membered cycloalkyl ring or a fused 4-, 5-, 6-,or 7-membered heterocycloalkyl ring, each optionally substituted by 1,2, or 3 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), C(═NR^(g2))NR^(c2)R^(d2),NR^(c2)C(═NR^(g2))NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), aryl, cycloalkyl,heteroaryl, and heterocycloalkyl; R^(A) is H, C₁₋₄ alkyl, C₂₋₄ alkenyl,or C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl,is optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, and C₁₋₄ alkyl; R^(B) is H, C₁₋₄alkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄alkenyl, or C₂₋₄ alkynyl, is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, and C₁₋₄alkyl; R^(C) and R^(D) are independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, or C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, orC₂₋₄ alkynyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, and C₁₋₄ alkyl; orR^(C) and R^(D) together with the N atom to which they are attached forma 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group,each optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, and C₁₋₄ alkyl; R^(a), R^(a1),R^(a2), are R^(a3) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy; R^(b), R^(b1), R^(b2), are R^(b3) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereinsaid C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, CN, amino, halo,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆haloalkoxy; R^(c) andR^(d) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy; or R^(c) and R^(d) together with the Natom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, CN, amino,halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy; R^(c1)and R^(d1) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy; or R^(c1) and R^(d1) together with the Natom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, CN, amino,halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, and C₁₋₆haloalkoxy; R^(c2)and R^(d2) are independently selected from H, C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl,arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl, whereinsaid C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,C(O)OR^(a3), C(O)R^(b3), S(O)₂R^(b3), alkoxyalkyl, and alkoxyalkoxy; orR^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl,heteroaryl, C(O)OR^(a3), C(O)R^(b3), S(O)₂R^(b3), alkoxyalkyl, andalkoxyalkoxy; R^(e) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, orheterocycloalkylalkyl; R^(f) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl; R^(g), R^(g1), and R^(g2) are independently selectedfrom H, CN, and NO₂; R^(h) and R^(i) are independently selected from Hand C₁₋₆ alkyl; and R^(j) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.2. The compound of claim 1, or pharmaceutically acceptable salt thereof,wherein Cy¹ is aryl or heteroaryl, each optionally substituted by 1, 2,3, 4, or 5 -W—X—Y—Z.
 3. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein Cy¹ is aryl or heteroaryl, eachoptionally substituted by 1, 2, 3, 4, or 5 -Z.
 4. The compound of claim1, or pharmaceutically acceptable salt thereof, wherein Cy¹ is aryl orheteroaryl, each optionally substituted by 1, 2, or 3 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, OH, andC₁₋₄ alkoxy.
 5. The compound of claim 1, or pharmaceutically acceptablesalt thereof, wherein Cy¹ is phenyl or quinolinyl, each optionallysubstituted by 1, 2, 3, 4, or 5 -W—X—Y—Z.
 6. The compound of claim 1, orpharmaceutically acceptable salt thereof, wherein Cy² is aryl orheteroaryl, each optionally substituted by 1, 2, 3, 4, or 5-W′—X′—Y′—Z′.
 7. The compound of claim 1, or pharmaceutically acceptablesalt thereof, wherein Cy² is phenyl optionally substituted by 1, 2, 3,4, or 5 -W′—X′—Y′—Z′.
 8. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein Cy² is phenyl optionally substituted by1, 2, 3, 4, or 5 -Z′.
 9. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein A is H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, NO₂, OR^(A), or NR^(C)R^(D).
 10. The compound of claim 1,or pharmaceutically acceptable salt thereof, wherein A is H orNR^(C)R^(D).
 11. The compound of claim 1, or pharmaceutically acceptablesalt thereof, wherein R¹ and R² together with the carbon atom to whichthey are attached form a 3- to 7-membered cycloalkyl group optionallysubstituted by 1, 2, 3, 4, or 5 substituents independently selected fromQ, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl is optionallysubstituted with 1, 2, or 3 substituents selected from Q, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d). 12.The compound of claim 1, or pharmaceutically acceptable salt thereof,wherein R¹ and R² together with the carbon atom to which they areattached form a cyclopropyl group optionally substituted by 1, 2, 3, 4,or 5 substituents independently selected from Q, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d), NR^(c)C(O)OR^(a),C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d), P(R^(f))₂,P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl is optionallysubstituted with 1, 2, or 3 substituents selected from Q, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR_(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), C(═NR^(g))NR^(c)R^(d), NR^(c)C(═NR^(g))NR^(c)R^(d),P(R^(f))₂, P(OR^(e))₂, P(O)R^(e)R^(f), P(O)OR^(e)OR^(f), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d). 13.The compound of claim 1, or pharmaceutically acceptable salt thereof,wherein R¹ and R² together with the carbon atom to which they areattached form a 3- to 7-membered cycloalkyl group.
 14. The compound ofclaim 1, or pharmaceutically acceptable salt thereof, wherein R¹ and R²together with the carbon atom to which they are attached form acyclopropyl group.
 15. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, having Formula II:


16. The compound of claim 1, or pharmaceutically acceptable saltthereof, having Formula IIIa or IIIb:


17. The compound of claim 1 selected from:3-[1-(4-Methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine(1);3-[1-(4-Methoxyphenyl)cyclopropyl]-7-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine(1);4-[1-(6-Phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]phenol(2);4-[1-(7-Phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]phenol(2);6-(4-Fluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(3);7-(4-Fluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(3); 3-[1-(4-Methoxyphenyl)cyclopropyl]-6-(4-morpholin-4-ylphenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (4);3-[1-(4-Methoxyphenyl)cyclopropyl]-7-(4-morpholin-4-ylphenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (4);6-(4-Chlorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(5);7-(4-Chlorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(5);4-3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylphenol(6);4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}phenol(6);4-3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylbenzonitrile(7);4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}benzonitrile(7);N-(4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}phenyl)acetamide(8);N-(4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}phenyl)acetamide(8);6-(4-Methoxyphenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(9);7-(4-Methoxyphenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(9);6-(2,4-Difluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(10);7-(2,4-Difluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(10);6-(3,4-Dichlorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(11);7-(3,4-Dichlorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(11);6-(3,4-Difluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(12);7-(3,4-Difluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(12);6-(3-Methoxyphenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(13);7-(3-Methoxyphenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(13);6-(3-Bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(14);7-(3-Bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(14);6-(5-Bromo-2-thienyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(15);7-(5-Bromo-2-thienyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(15);3-[1-(4-Methoxyphenyl)cyclopropyl]-6-(4-nitrophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine(16);3-[1-(4-Methoxyphenyl)cyclopropyl]-7-(4-nitrophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine(16);6-(4-Bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(17);7-(4-Bromophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(17);4-3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylaniline(18);4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}aniline(18);3-[1-(4-Methoxyphenyl)cyclopropyl]-6-[3-(1-methyl-1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(19);3-[1-(4-Methoxyphenyl)cyclopropyl]-7-[3-(1-methyl-1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(19);3-[1-(4-Methoxyphenyl)cyclopropyl]-6-[3-(1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(20);3-[1-(4-Methoxyphenyl)cyclopropyl]-7-[3-(1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(20); tert-Butyl(3′-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylbiphenyl-4-yl)carbamate(21); tert-Butyl(3′-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-yl}biphenyl-4-yl)carbamate(21);3-[1-(4-Methoxyphenyl)cyclopropyl]-6-[4-(1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(22);3-[1-(4-Methoxyphenyl)cyclopropyl]-6-[4-(1-methyl-1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(23);3-[1-(4-Bromophenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine(24);3-[1-(3-Bromophenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine(25);3-[1-(4-Methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine(26);6-[1-(6-Phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]quinoline(27); 3-[1-(4-Chlorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (28);3-[1-(2,4-Dichlorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine(29); 3-[1-(3-Bromophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (30);3-[1-(4-Bromophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (31);3-[1-(2-Chlorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (32);6-(4-Fluorophenyl)-3-[1-(2-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(33);6-(4-Fluorophenyl)-3-[1-(3-fluorophenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(34);6-(4-Fluorophenyl)-3-{1-[3-(trifluoromethyl)phenyl]cyclopropyl}[1,2,4]triazolo[4,3-b][1,2,4]triazine(35); 3-[1-(2-Chloro-6-fluorophenyl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (36);3-[1-(1,3-Benzodioxol-5-yl)cyclopropyl]-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine(37);4-{1-[6-(4-Fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(38);6-{1-[6-(4-Fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(39);6-{1-[6-(3-Bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(40);6-{1-[6-(4-Bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline(41);3-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzonitrile(42);4-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzonitrile(43);3-[1-(4-Methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-amine(44);6-(4-Fluorophenyl)-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-7-amine(45);6-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-1,3-benzothiazol-2-amine(46);1-(4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}phenyl)pyrrolidin-2-one(47);N-Cyclopropyl-4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzamide(48);4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-(tetrahydro-2H-pyran-4-yl)benzamide(49);N-(trans-4-Hydroxycyclohexyl)-4-3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-ylbenzamide(50) Ethyl4-[(4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]piperidine-1-carboxylate(51);4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-(pyridin-2-ylmethyl)benzamide(52); Ethyl1-[(4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]cyclopropanecarboxylate(53);N-[1-(6-Fluoropyridin-2-yl)pyrrolidin-3-yl]-4-{3-[1-(4-methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzamide(54);4-{3-[1-(4-Methoxyphenyl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl-N′-pyridin-2-yl}benzohydrazide(55);6-(1-{6-[3-(1H-imidazol-1-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline(56);6-(1-{6-[4-(1H-imidazol-1-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline(57);3-{4-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1,3-oxazolidin-2-one(58);6-(1-{6-[3-(6-Methoxypyridin-3-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline(59); N,N-Dimethyl-5-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridine-2-carboxamide(60); N-Ethyl-5-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridine-2-carboxamide(61);N-Methyl-2-(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide(62);2-(4-{3-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide(63);N-(1-Pyridin-2-ylethyl)-2-(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide(64); N,N-Dimethyl-2-(4-{3-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide(65);N-Methyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide(66); N-Isopropyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide(67);N-(Cyclopropylmethyl)-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)acetamide(68);N-Isopropyl-2-methyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)propanamide(69);6-[1-(6-{4-[1-(1,1-Dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]phenyl}[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]quinoline(70); (2R)—N,N-Dimethyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)propanamide(71); (2S)—N,N-Dimethyl-2-(4-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-1H-pyrazol-1-yl)propanamide(72);6-(3-Bromophenyl)-3-[1-(3-methyl[1,2,4]triazolo[4,3-a]pyridin-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazine(73); 6-1-[6-(4-Bromo-3-fluorophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropylquinoline (74);6-(1-{6-[3-Fluoro-4-(1H-imidazol-1-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline(75);5-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}-N,N-dimethylpyridine-2-carboxamide(76);5-{2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridin-2-amine(77); Methyl(5-{2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridin-2-yl)carbamate(78); 3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl]-6-(4-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (79);4-{3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-{(1S)-1-[(dimethylamino)carbonyl]propyl}benzamide(80);4-{3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-{(1S)-1-[(dimethylamino)carbonyl]-2-methylpropyl}benzamide(81);4-{3-[1-(1,3-Benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}-N-{(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl}benzamide(82);6-(1-{6-[4-(1-Methyl-1H-pyrazol-4-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline(83);N-Methyl-5-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridine-2-carboxamide(84); N,N-Dimethyl-5-{4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]phenyl}pyridine-2-carboxamide(85);6-(1-{6-[4-(1H-pyrazol-1-yl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline(86); N-(Cyclopropylmethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide (87);N-Ethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide (88);N,N-Dimethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide (89);N-Cyclopropyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(90); N-(Pyridin-2-ylmethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide (91); Ethyl4-{4-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoyl}piperazine-1-carboxylate(92);6-(1-{6-[4-(Pyrrolidin-1-ylcarbonyl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline(93);6-[1-(6-{4-[(3,3-Difluoropyrrolidin-1-yl)carbonyl]phenyl}[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)cyclopropyl]quinoline(94); 6-{1-[6-(4-{[3-(3-Fluorophenyl)pyrrolidin-1-yl]carbonyl}phenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline (95);6-{1-[6-(4-{[(3S)-3-Fluoropyrrolidin-1-yl]carbonyl}phenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline (96);4-[3-(1-Quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]benzamide(97);N-(1-Pyridin-2-ylcyclopropyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(98);N-(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(99);N-{(1S)-1-[(Dimethylamino)carbonyl]-2,2-dimethylpropyl}-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(100);N-[(1S)-1-(Azetidin-1-ylcarbonyl)-2,2-dimethylpropyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(101);N-[(1S)-2-Amino-1-methyl-2-oxoethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(102);N-[(1S)-1-(Aminocarbonyl)-2-methylpropyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(103);N-Ethyl-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(104);2-Fluoro-N-methyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(105);2-Fluoro-N-(trans-4-hydroxycyclohexyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(106);2-Fluoro-N-(2-methoxy-1,1-dimethylethyl)-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(107);N-Cyclopropyl-2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(108); 2-Fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide (109);2-Fluoro-N,N-dimethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(110);6-(1-{6-[3-Fluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl}cyclopropyl)quinoline(111);N-Methyl-N-2-[methyl(pyridin-2-yl)amino]ethyl-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(112);N-[(1R)-1-(4-Methyl-1,3-thiazol-2-yl)ethyl]-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzamide(113); or pharmaceutically acceptable salt thereof.
 18. A compositioncomprising a compound of claim 1, or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 19. A method ofinhibiting activity of a receptor tyrosine kinase comprising contactingsaid kinase with a compound of claim 1, or pharmaceutically acceptablesalt thereof.
 20. The method of claim 19 wherein said kinase belongs tothe Met or FLK subfamilies.
 21. The method of claim 20 wherein saidkinase is c-Met, KDR, or flt-3 kinase.
 22. The method of claim 21wherein said kinase is c-Met.
 23. A method of inhibiting the HGF/c-Metkinase signaling pathway in a cell comprising contacting said cell witha compound of claim 1, or pharmaceutically acceptable salt thereof. 24.A method of inhibiting the proliferative activity of a cell comprisingcontacting said cell with a compound of claim 1, or pharmaceuticallyacceptable salt thereof.
 25. A method of inhibiting tumor growth in apatient comprising administering to said patient a therapeuticallyeffective amount of a compound of claim 1, or pharmaceuticallyacceptable salt thereof.
 26. A method of inhibiting tumor metastasis ina patient comprising administering to said patient a therapeuticallyeffective amount of a compound of claim 1, or pharmaceuticallyacceptable salt thereof.
 27. A method of treating a disease in apatient, wherein said disease is associated with dysregulation of theHGF/c-MET signaling pathway, comprising administering to said patient atherapeutically effective amount of a compound of claim 1, orpharmaceutically acceptable salt thereof.
 28. The method of claim 27wherein said disease is cancer, atherosclerosis, lung fibrosis, renalfibrosis and regeneration, liver disease, allergic disorder,inflammatory disease, autoimmune disorder, cerebrovascular disease,cardiovascular disease, or condition associated with organtransplantation.
 29. A method of treating a cancer in a patientcomprising administering to said patient a therapeutically effectiveamount of a compound of claim 1, or pharmaceutically acceptable saltthereof.
 30. The method of claim 29 wherein said cancer is a carcinoma,musculoskeletal sarcoma, soft tissue sarcoma, or hematopoieticmalignancy.
 31. The method of claim 29 wherein said cancer is bladdercancer, breast cancer, cervical cancer, cholangiocarcinoma cancer,colorectal cancer, esophageal cancer, gastric cancer, head and neckcancer, cancer of the kidney, liver cancer, lung cancer, nasopharygealcancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroidcancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma,MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma, multiple myeloma,lymphoma, adult T cell leukemia, acute myelogenous leukemia, chronicmyeloid leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma, orWilm's tumor.